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Journal of Crohn's and Colitis (2008) 2, 24–62

ava i l a b l e a t w w w. s c i e n c e d i r e c t . c o m

SPECIAL ARTICLE

European evidence-based Consensus on the management of ulcerative colitis: Current management
S.P.L. Travis ⁎,1, E.F. Stange ⁎,1, M. Lémann, T. Øresland, W.A. Bemelman, Y. Chowers, J.F. Colombel, G. D'Haens, S. Ghosh, P. Marteau, W. Kruis, N.J.McC. Mortensen, F. Penninckx, M. Gassull for the European Crohn's and Colitis Organisation (ECCO)
Received 23 November 2007; accepted 23 November 2007

KEYWORDS
Ulcerative colitis; Acute severe colitis; Mesalazine; Azathioprine; Infliximab; Ileal pouch-anal anastomosis

Contents 5. Medical management of active ulcerative colitis. . . . . . . . . . . . . . . . . ............... 5.1. General . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............... 5.1.1. Disease activity. . . . . . . . . . . . . . . . . . . . . . . . . . . ............... 5.1.2. Approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............... 5.2. Treatment according to site of disease and disease activity . . . . . . . ............... 5.2.1. Proctitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............... 5.2.2. Left sided colitis . . . . . . . . . . . . . . . . . . . . . . . . . . ............... 5.2.3. Extensive ulcerative colitis . . . . . . . . . . . . . . . . . . . . ............... 5.2.4. Severe ulcerative colitis of any extent. . . . . . . . . . . . . . ............... 5.2.5. Intravenous-steroid resistant ulcerative colitis of any extent . . . . . . . . . . . . . . . . . . . . . . 5.2.6. Toxic dilatation and complications of severe ulcerative colitis . . . . . . . . . . . . . . . . . . . . . 5.2.7. Refractory proctitis and distal colitis . . . . . . . . . . . . . . ............... . . . . . . . . . ... ... ... ... ... ... ... ... ... 29 31 .... . . . . . . . . . . . . . . . . . . 26 26 26 26 26 26 27 27 28

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⁎ Corresponding authors. Travis is to be contacted at John Radcliffe Hospital, Oxford, OX3 9DU, UK. Tel.: +44 1865 228753; fax: +44 1865 228763. Stange, Department of Internal Medicine 1, Robert Bosch Krankenhaus, PO Box 501120 Auerbachstr, 110, 70341 Stuttgart, Germany. Tel.: +49 711 81013404; fax: +49 711 81013793. E-mail addresses: simon.travis@ndm.ox.ac.uk (S.P.L. Travis), Eduard.Stange@rbk.de (E.F. Stange). 1 These authors acted as convenors of the Consensus and contributed equally to the work. 1873-9946/$ - see front matter © 2007 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.crohns.2007.11.002

ECCO Consensus on UC: Current management 5.3. Treatment according to the course or behaviour of disease . . . . . . . . . . ............... 5.3.1. Treatment of relapse compared to new cases . . . . . . . . . . . . . ............... 5.3.2. Early relapse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............... 5.3.3. ‗Steroid-dependent‘, active ulcerative colitis . . . . . . . . . . . . . ............... 5.3.4. Oral steroid-refractory ulcerative colitis . . . . . . . . . . . . . . . . ............... 5.3.5. Immunomodulator-refractory ulcerative colitis . . . . . . . . . . . . ............... 5.4. Therapy-specific considerations . . . . . . . . . . . . . . . . . . . . . . . . . . ............... 5.4.1. Aminosalicylates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............... 5.4.2. Corticosteroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............... 5.4.3. Infliximab (IFX) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............... 5.4.4. Other biological therapy . . . . . . . . . . . . . . . . . . . . . . . . . ............... 5.4.5. Thiopurines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............... 5.4.6. Methotrexate (MTX) . . . . . . . . . . . . . . . . . . . . . . . . . . . ............... 5.4.7. Calcineurin inhibitors (ciclosporin (CsA) and tacrolimus) . . . . . . . ............... 5.4.8. Alternative therapies whose role remains to be established . . . . . ............... 5.5. Preparation for the period after treatment of active disease . . . . . . . . . ............... 6. Maintenance of remission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............... 6.1. General . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............... 6.1.1. Maintenance therapy trial design . . . . . . . . . . . . . . . . . . . . ............... 6.1.2. Pattern of disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............... 6.1.3. Risk factors for relapse . . . . . . . . . . . . . . . . . . . . . . . . . ............... 6.2. Medications for maintenance of remission . . . . . . . . . . . . . . . . . . . . ............... 6.2.1. Aminosalicylates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............... 6.2.2. Thiopurines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............... 6.2.3. Infliximab (IFX) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............... 6.2.4. Probiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............... 6.2.5. Other treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............... 6.3. Duration of maintenance therapy . . . . . . . . . . . . . . . . . . . . . . . . . ............... 7. Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............... 7.1. General . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............... 7.2. Technical considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............... 7.2.1. Surgery for acute severe colitis . . . . . . . . . . . . . . . . . . . . . ............... 7.2.2. Managing the rectal remnant . . . . . . . . . . . . . . . . . . . . . . ............... 7.2.3. Site of anastomosis for restorative poctocolectomy . . . . . . . . . ............... 7.2.4. Anastomostic technique for restorative proctocolectomy . . . . . . ............... 7.2.5. Site of anastomosis for neoplasia complicating colitis . . . . . . . . . ............... 7.2.6. Role of covering ileostomy for restorative proctocolectomy . . . . . . ............... 7.2.7. Number of procedures to maintain competency. . . . . . . . . . . . ............... 7.2.8. Salvage surgery for pouches . . . . . . . . . . . . . . . . . . . . . . . ............... 7.3. Follow-up . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............... 7.3.1. General pouch follow up. . . . . . . . . . . . . . . . . . . . . . . . . ............... 7.3.2. Pouch surveillance . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............... 7.4. Fertility and delivery in patients with a restorative proctocolectomy . . . . ............... 7.4.1. Impact of pelvic surgery on fecundity . . . . . . . . . . . . . . . . . ............... 7.4.2. Mode of delivery for patients with restorative proctocolectomy . . . . . . . . . . . . . . . . . . . . 50 7.5. Surgical choices in addition to restorative proctocolectomy . . . . . . . . . . ............... 7.5.1. Age . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............... 7.5.2. Continent ileostomy . . . . . . . . . . . . . . . . . . . . . . . . . . . ............... 7.5.3. Ileorectal anastomosis . . . . . . . . . . . . . . . . . . . . . . . . . . ............... 7.5.4. Cancer surveillance of the rectal remnant after colectomy . . . . . . . ............... 7.5.5. Pouch excision after pouch failure . . . . . . . . . . . . . . . . . . . ............... 7.5.6. Laparoscopic pouch surgery . . . . . . . . . . . . . . . . . . . . . . . ............... 7.5.7. Pouch surgery for indeterminate colitis, or IBD yet-to-be classified . . . . . . . . . . . . . . . . . . 51 7.6. Surgery and medication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............... 7.6.1. Perioperative prednisolone . . . . . . . . . . . . . . . . . . . . . . . ............... 7.6.2. Perioperative azathioprine. . . . . . . . . . . . . . . . . . . . . . . . ............... 7.6.3. Perioperative anti-TNF therapy . . . . . . . . . . . . . . . . . . . . . ............... 7.7. Colectomy in practice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............... Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............... Acknowledgements. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............... References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 32 32 32 32 32 35 35 36 36 37 37 37 38 38 39 39 39 39 39 39 40 40 43 44 45 46 47 47 47 47 47 48 48 48 48 49 49 49 49 49 49 50 50 50 50 50 51 51 51 51 51 51 52 52 52 52 53 53

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S.P.L. Travis et al. (such as mesalazine preparations, budesonide, or types of enema). The choice is influenced by the balance between drug potency and side-effects; previous response to treatment (especially when considering treatment of a relapse, treatment of steroid-dependent or -refractory disease, or immunomodulator-refractory disease, Section 5.3); and the presence of extraintestinal manifestations (indicating the need for systemic therapy).

5. Medical management of active ulcerative colitis
5.1. General
The general principles for treating active ulcerative colitis are to consider the activity, distribution (proctitis, left-sided, extensive,1 and pattern of disease (relapse frequency, course of disease, response to previous medications, side-effect profile of medication, extra-intestinal manifestation), before treatment decisions are made in conjunction with the patient. 5.1.1. Disease activity The principal scoring systems used for clinical trials are covered in Section 5.1.2 and have been comprehensively reviewed.2 Some additional points are clinically relevant. In clinical practice it matters most to distinguish severe ulcerative colitis necessitating hospital admission from those with mild or moderate disease who can generally be treated as outpatients. The simplest, best validated and most widely used index for identifying acute severe 3: any patient who UC remains that of Truelove & Wi_tts has a bloody stool frequency ≥6/day and a tachycardia (N90 bpm), or temperature N37.8 °C, or anaemia (haemoglobin b10.5 g/dL), or an elevated ESR (N30 mm/ h) has severe ulcerative colitis (Table 1.3). This index has been used in 20/32 studies of intensive intravenous treatment for severe UC.4 Only one additional criterion in addition to the bloody stool frequency ≥6/day is needed to define a severe attack.5 While these criteria have the major limitation of being unresponsive and cannot track the course of disease, they do distinguish the severe from the moderate or mild and have value in everyday practice because they are easy to use, which no other index achieves. It should be standard practice to confirm active colitis by sigmoidoscopy or proctoscopy before starting treatment. Rectal mucosal biopsy helps exclude unexpected causes of symptoms similar to active disease (such as cytomegalovirus, amoebic, or other infection, rectal mucosal prolapse, Crohn's disease, or even irritable bowel syndrome and haemorrhoidal bleeding). 5.1.2. Approach Patients should be encouraged to participate actively in therapeutic decisions. In a systematic review of clinical trials, a mean 15% (95%CI 10–21%) of patients entered remission when receiving placebo.9 Prescribing no treatment, however, is rarely an option, because rectal bleeding and urgency are sufficiently concerning to the patient to justify topical therapy even if no systemic therapy is recommended. The appropriate choice of medication depends on many factors that are best tailored to the individual. Despite general agreement that treatment decisions for active UC should be based on the distribution, activity and pattern of disease, numbers in clinical trials often become too small for statistically valid conclusions to be drawn when patients are stratified according to the distribution and pattern of disease.7 Different galenic preparations are released at different sites and may have local activity

5.2. Treatment according to site of disease and disease activity
5.2.1. Proctitis

ECCO statement 5A Mesalazine 1 g suppository daily is the preferred initial treatment for mild or moderately active proctitis [EL1b, RG B]. Mesalazine foam enemas are an effective alternative [EL1b]. Suppositories may deliver drug more effectively to the rectum and are better tolerated than enemas [EL3, RG C]. Combining topical mesalazine with oral mesalazine or topical steroid, may be more effective than either alone and should be considered for escalation of treatment [EL1b, RG B]. Oral mesalazine alone is less effective [EL1b]

Active colitis limited to the rectum should first be treated topically. Suppositories are more appropriate than enemas, because suppositories target the site of inflammation; only 40% of foam enemas and 10% of liquid enemas can be detected in the rectum after 4 hr.10 Topical mesalazine (5-ASA) induced remission in active proctitis and distal colitis in 31–80% (median 67%) compared to 7– 11% given placebo in a meta-analysis of 11 trials in 778 patients.11 Topical mesalazine is at least twice as effective as topical steroids whether for symptoms (OR 2.42, 95%CI 1.72–3.41), endoscopy (OR 1.89, 95%CI 1.29–2.76), or histology (OR 2.03, 95%CI 1.28–3.20).12 Mesalazine suppositories 1 g daily are highly effective.13 There is no dose response to topical therapy above a dose of 1 g mesalazine daily. Clinical (and endoscopic) remission can occur in up to 64% (52%) within 2 weeks.13 Topical steroids should be reserved as second line therapy for patients who are intolerant of topical mesalazine.14 Topical mesalazine is more effective than oral mesalazine for proctitis,15 but the combination of oral and topical mesalazine may be better than either alone for colitis b50 cm from the anal verge.16 There have been no trials on combination therapy for proctitis alone. Combining topical mesalazine and steroids also helps: beclomethasone dipropionate (3 mg) and mesalazine (2 g) enemas produced significantly better clinical, endoscopic and histological improvement than either agent alone.17 Patients who fail to improve on topical mesalazine and topical corticosteroids should be treated with additional oral mesalazine or, alternatively, oral prednisolone, as if the colitis was more extensive or severe (below). Treatment of refractory proctitis is discussed in Section 5.2.7.

RG B]. Oral mesalazine is effective. Once and twice daily dosing produced similar results. Oral aminosalicylates alone induce remission only in a minority of patients [EL1a.19.7% respectively (ns). with remission rates of 29% and 34% respectively. RG B] combined with oral mesalazine N 2 g/day [EL1a. MMx 1. and NNT=4 to induce response or remission (95% CI 3–6)22).1). There was a trend for mesalazine to be better than sulfasalazine for endoscopic improvement (OR 0. Systemic corticosteroids are appropriate if symptoms of active colitis do not respond rapidly to mesalazine [EL1b.23. then the response can be said to be slow and therapy augmented.22 Two further placebo controlled trials of a multimatrix mesalazine formulation for mild-moderate UC have been published more recently.2.8 g group and 59.24 Clinical and endoscopic remission was achieved in 40. RG B] The approach is similar to that described for left-sided colitis. RG A]. Oral aminosalicylates alone are less effective [EL1a. mild-to-moderate UC. Severe left-sided colitis is usually an indication for hospital admission for intensive treatment with systemic therapy [EL1b. RG B] Combined oral and topical mesalazine therapy is recommended. with the important caveat that there should be a lower threshold for decisive treatment with systemic steroids.8 g once daily. if a . 95%CI 0.53).8 Treatment worked just as well for left-sided disease as for extensive colitis. beclomethasone diproprionate 5 mg/day had an effect similar to that of 2.18 evidence that topical therapy achieves higher rectal mucosal 5ASA concentrations than oral therapy19 and is associated with improved clinical outcome.66. The US concern about steroid-induced side-effects is shared by their patients. Treatment response was 71. Meta-analysis of mesalazine for active UC shows a doseresponse for improvement from b2. Most therapeutic trials of mild or moderate active colitis include patients with any disease distribution other than proctitis. Similarly. showing it to work more rapidly and effectively.4 g/day once daily and 41.18 This confirms that added benefit of topical mesalazine for extensive colitis.ECCO Consensus on UC: Current management 5. or placebo for 8 weeks.2.24 as well as a combined analysis.21 This trend is confirmed by a trial of 4.2% given 4. The practice in many European countries is to introduce oral steroids at an early stage. but not for remission.60–1. RG C]. Late introduction of steroids selects a more refractory population. Extensive ulcerative colitis 27 ECCO statement 5B Left-sided active ulcerative colitis of mild-moderate severity should initially be treated with topical aminosalicylates [EL1b. This gives a useful timescale for determining the speed of response.25 The first study randomized 280 patients to either MMx 4. because aminosalicylates cannot match the speed of response for patients suffering miserable symptoms. Topical mesalazine is more effective than topical steroid [EL1a.20 are consistent with the recommendation. RG A]. but not significantly better than sulphasalazine (OR 0. RG A]. Oral mesalazine (Pentasa®) 4 g/day with a 1 g mesalazine enema in 116 patients induced clinical remission by 8 weeks in 64% compared to 43% on oral mesalazine alone (p = 0.42–1. RG A]. so higher doses of mesalazine are recommended for moderately active colitis.04) and mesalazine is better tolerated than sulfasalazine. which usually means decisive treatment with steroids.83. The primary endpoint was remission at 8 weeks. combined with topical mesalazine [EL1b.40. RG C]. but both oral and topical aminosalicylates (mesalazine) are effective for left-sided colitis.01)23 (see also Section 6. A systematic review of 9 placebo controlled trials of oral aminosalicylates for active ulcerative colitis showed the overall remission rate to be only 20%.3.0 g ECCO statement 5C Extensive ulcerative colitis of mild-moderate severity should initially be treated with mesalazine N2 g/day [EL1a. If rectal bleeding persists beyond 10–14 days. but less effective than combination therapy [EL1b.9 g and N3. although remission rates were only 20.8 g/day once daily compared to 22. In the largest and most recent study of 177 patients with active left-sided or extensive colitis.2% and 17. In a meta-analysis of oral 5-ASA compounds for active colitis.27 but combination with topical mesalazine is better. or who are already taking appropriate maintenance therapy.21 This is a modest benefit — (NNT to induce remission=10 (95% CI 7–21).036). RG A].002). 95%CI 0.4 g mesalazine daily in 268 patients with moderately active UC. There is something of a transatlantic divide on the threshold for using steroids.30–0.21 mesalazine was more than twice as effective as placebo (OR 0.01 and 0. A peripheral benefit is a reduction in the median time to cessation of rectal bleeding (from 16 days to 9 days (pb 0.8% in the 4.4 g mesalazine.8 g mesalazine (Asacol®) vs 2. Topical steroids or mesalazine alone are also effective.2% in the 2. but may also be selffulfilling.14 There has been just one trial on 60 patients of combined therapy for distal colitis compared to oral or topical therapy alone.007 respectively) and 32. Failure of mild or moderately active disease to respond within 2 weeks to mesalazine is an indication to consider oral prednisolone.5% given MMx mesalazine 2.26 5. Steroids with a colonic release mechanism and low systemic bioavailabilty such as beclomethasone diproprionate or budesonide are becoming available. half of whom had distal disease. Systemic corticosteroids are appropriate if symptoms of active colitis do not respond rapidly to mesalazine [EL1b.4 g group (p=0. 2. but without systemic steroid side-effects.05)) at the higher dose.16 However. extrapolation from a trial of combination therapy for extensive colitis. 95%CI 0.6% given Asacol® (ns).0–2.13) for the failure to induce global clinical improvement or remission.2.2 g twice daily. RG A]. Left sided colitis daily (p=0.2.03). A further placebo-controlled study compared MMx mesalazine with Asacol® in 346 patients with active.0 g. Severe extensive colitis is usually an indication for hospital admission for intensive treatment [EL1b. and there was no increase in side-effects at the higher dose. compared to 13% on placebo (pb 0.1% on placebo (p=0.

Hb b 10. 95% CI 0. the overall response to steroids (intravenous hydrocortisone.2. An appropriate regimen for moderately active disease is prednisolone 40 mg/day for 1 week. if it becomes necessary. it was not possible to discriminate between complete and partial responses to steroids.3. so that steroid-dependence is recognised at an early stage and a decision to start immunomodulators is facilitated. with colonic release mechanisms) are available or being developed. p = 0. Patients with bloody diarrhoea ≥ 6/day and signs of systemic toxicity (tachycardia N 90 bpm. Mortality was 1% (22/1991. and when to start rescue medical therapy in time so that surgery. compared to 24% in the placebo group3 and it is now b1% in specialist centres. Shorter courses (b3 weeks) are associated with early relapse and doses of prednisolone b15 mg day are ineffective for active disease.4. RG D] with intravenous steroids (such as methylprednisolone 60 mg or hydrocortisone 400 mg daily) [EL1b.4. fever N37. The principal clinical dilemmas are how to identify at an early stage those who are likely to need colectomy.2. Only one patient in a hundred need die as a result of complications caused by operating too late to negate any benefits of medical therapy. Intravenous corticosteroids remain the mainstay of conventional therapy for acute severe colitis. or an ESR N 30 mm/h) should be admitted to hospital for intensive treatment [EL5. Corticosteroids are generally given intravenously using. Travis et al. so too does the opportunity for procrastinating about surgical decisions.3.4 In a systematic review of 32 trials of steroid therapy for acute severe colitis involving 1991 patients from 1974–2006. S. Severe ulcerative colitis of any extent Acute severe ulcerative colitis is a potentially life-threatening condition. for example. the response to steroids of severe colitis has remained unchanged for 50 years. Because of substantial heterogeneity. compared to 48% treated with 8 g/day sulphasalazine and steroid enemas.5 g/dL.8%) first attacks and 109/619 (17. Treatment with oral and rectal corticosteroids is based on two early studies on active UC of any extent. but it is sensible to have a standard approach at any single centre. Patients are best cared for jointly by a gastroenterologist and colorectal surgeon [EL5. 565 (29%. ECCO statement 5D Severe active ulcerative colitis is best defined by Truelove and Witts' criteria [EL3.6%) of all patients have a severe attack as defined by the criteria in Statement 5D.07.4.1. The reason for this proactive approach is the risk of complications (including toxic dilatation) in patients with extensive disease who are under-treated.4 Out of the 1991 patients. 30 mg/day for 1 week. Monotherapy with intravenous ciclosporin (to achieve a minimum therapeutic concentration) [EL1b.37 Bolus injection is as effective as continuous infusion. Only a minority (100/1991) received ciclosporin (below).8). since extending therapy beyond 7 to 10 days carries no benefit. 95% CI 28–31%) came to colectomy. 5. Other measures are considered appropriate in addition to intravenous steroids: · Intravenous fluid and electrolyte replacement to correct and prevent dehydration or electrolyte imbalance.30 Oral steroids with low systemic bioavailability (budesonide or prednisolone metasulphobenzoate.P.4. methylprednisolone.6 In 1955 the introduction of steroid therapy reduced mortality of severe colitis to 7%. As therapeutic options increase (ciclosporin.2.7–1.5. RG B]. 5. RG D] Treatment with corticosteroids should not be delayed awaiting microbiological results for possible infective causes. Investigations on admission. including extensive colitis. but lower doses are less effective. with steroid enemas) induced remission in 77% of 118 patients with mild to moderate disease within 2 weeks. In 1933. the Consensus believes that patients meeting these criteria are best admitted to hospital for intensive treatment. or betamethasone) was 67% (95%CI 65– 69%.6%) and none of these outcomes changed between 1974 and 2006 (R2 = 0. Many different regimes are used. ECCO statement 5E Severe active ulcerative colitis with signs of systemic toxicity should be treated in hospital [EL5.L.36 although details (such as the value of antibiotics or parenteral nutrition) are debated by some. methylprednisolone 40 mg or hydrocortisone 100 mg four times daily. The two are not mutually exclusive and management demands the most taxing clinical judgement. or 1429/1991). decisive treatment with steroids is considered appropriate. RG C] is an option for patients intolerant of intravenous steroids.4. See Section 7.29 who found the combination of oral and rectal steroids to be better than either alone.28 Similar findings were reported by Lennard-Jones. Management involves more than pharmacotherapy.38 Treatment is usually given for about 5 days.8 °C.32 5. tacrolimus. RG C].2.28 patient already on mesalazine N2 g/day or immunomodulators as maintenance therapy has a relapse. or infliximab among others). Oral prednisolone (starting at 40 mg daily.4 In view of this and the 29% colectomy rate (95%CI 28–31%4). Conventional therapy. is not inappropriately delayed. The only prevalence data date from 1963: 47/ 250 (18.2.3. RG D] .35 Nevertheless. This is why it is recommended that patients should be treated in hospital jointly by a specialist Gastroenterologist and Colorectal surgeon. 5.33 To grasp the implications of current medical and surgical therapy requires knowledge of the historical context. Therapeutic approach. then 20 mg/day for 1 month before decreasing by 5 mg/ day/week. 16/21 (75%) died in the first year after acute presentation with ulcerative colitis in Birmingham34 and in 1950 a mortality of 22% was reported from Oxford among 129 cases in the first year after diagnosis.31. Higher doses (including 500 mg–1 g methylprednisolone) are no more effective.

60 but this is not widely used in clinical practice.39 Topical therapy (corticosteroids or mesalazine) if tolerated and retained.42 but some centres use a food challenge after 5 days in an attempt to discriminate between complete and partial responders to intensive therapy. RG D]. which risk precipitating colonic dilatation. albumin and pH.58 This needs prospective validation. The CRP and stool frequency criteria5 are the simplest objective measure. as well as temperature in children with acute severe colitis predicted the need for colectomy. Stool cultures and assay for Cl difficile toxin. The question is how to do this safely.49 Furthermore. rather than relative measures. Consequently monotherapy with CsA is a useful option in those patients with severe colitis when steroids are best avoided. ciprofloxacin or vancomycin in acute colitis have shown no consistent benefit in addition to conventional therapy. first attack of short duration. Surgical options should be considered and discussed at this stage or earlier. colectomy should usually be recommended [EL5. An ESR N75 or a pyrexia N38 °C on admission have been associated with a 5–9-fold increase in the need for colectomy in a prospective study of 67 patients. without concomitant intravenous steroids. or infliximab [EL1b. in studies that developed a Pediatric UC Activity Index55. half of all patients in another study comparing low dose with high dose CsA50 also received CsA monotherapy.39 Sigmoidoscopy or proctosopy and biopsy to confirm the diagnosis and exclude cytomegalovirus infection.53 while a frequency N8/day on day 3 of intensive treatment predicted colectomy in 85% on that admission (‗Oxford index‘). · · · · Ciclosporin monotherapy (CsA. Third line therapy may be considered at a specialist centre on day 2 was associated with 55% colectomy.52 but they cannot be used for decision-making when colectomy is imminent. 4 mg/kg/day intravenously) is as effective as intravenous methylprednisolone (MeP) 40 mg/ day for acute severe colitis. or personal preference). or after recent admission to hospital). Factors that predict the need for colectomy in acute severe colitis can broadly be divided into clinical. but must be as straightforward so that a decision to start a calcineurin inhibitor.57 In this study. but it is becoming easier for physicians to aquiesce with every patient who does not want a colectomy as therapeutic options increase. lack of response to steroids was predicted by b40% reduction in stool frequency within 5 days.14CRP is N8 on day 3: ‗Sweden index‘) predicted colectomy in 75%. Biochemical markers include CRP. RG B] or tacrolimus [EL1b.5 This latter measure has been validated: a frequency N4 and CRP N25 mg/L on day 3 (or when the stool frequency × 0. such as those susceptible to steroid-psychosis (schizophrenics or previous psychosis). If there is clinical deterioration colectomy is recommended.ECCO Consensus on UC: Current management Potassium supplementation of at least 60 mmol/day is almost invariably necessary. developed a numerical score combining mean stool frequency over 3 days. No individual patient wants a colectomy. presence or absence of colonic dilatation and hypoalbuminaemia (b30 g/L) on admission that was associated with the need for colectomy in up to 85%. RG B] will often be appropriate. or proceed to colectomy is not inappropriately delayed. Second line therapy with either ciclosporin [EL1b. A retrospective study of 167 patients in whom a high proportion (40%) came to colectomy. diabetes. NSAID and opioid drugs.5 cm (associated with a 75% need for colectomy).). objective measures are needed to aid decisionmaking. or immediately prior to surgery. 29 · · · · ECCO statement 5F The response to intravenous steroids is best assessed objectively (by stool frequency. biochemical and radiological markers. but neither immutable nor always reproduced. Nevertheless. Intravenous-steroid resistant ulcerative colitis of any extent The timing of colectomy for severe colitis remains one of the most difficult decisions that a gastroenterologist has to make. Indices exist to be applied. RGB]. RG B]. tobramycin. CRP and stool frequency on day 3. Hypokalaemia or hypomagnesaemia can promote toxic dilatation.3). In a randomized trial there was a response in 10/15 CsA patients vs 8/15 MeP patients. Bowel rest through intravenous nutrition does not alter the outcome.5. or temperature.59 but only 50% in a prospective study from the same institution. or mucosal islands on a plain abdominal radiograph (75% colectomy).3. Radiological criteria include the presence of colonic dilatation N5. This means surgical consultation and assessment by a stomatherapist in addition to augmenting medical treatment.5 The depth of colonic ulceration after gentle air insufflation identified 42/ 49 patients with deep ulcers that were associated with the need for colectomy. 5. Enteral nutrition is most appropriate and associated with significantly fewer complications than parenteral nutrition in acute colitis (9% vs 35%41. or for some other reason (concomitant osteoporosis.2. antidiarrhoeal agents. Other criteria may do as well. Simple. Subcutaneous heparin to reduce the risk of thromboembolism. infliximab.54 More recently.53 The presence of an ileus (indicated by 3 or more small bowel loops of gas) was associated with colectomy in 73% in a retrospective study. CRP and abdominal radiography) on or about the third day [EL2b. Genetic polymorphisms have the potential to predict the outcome of disease in an individual from the time of diagnosis51. as a threshold for triggering appropriate action at an early stage.43–48 Blood transfusion to maintain a haemoglobin N10 g/dl. although there have been no systematic studies in acute severe colitis.56 (Section 11. A stool frequency N12/day . Clinical markers depend on the objective measures of stool frequency. Withdrawal of anticholinergic.40 Nutritional support if the patient is malnourished. There are two principal options that can be added to intravenous steroids: calcineurin inhibitors (ciclosporin or tacrolimus) or infliximab (IFX). If there is no improvement within a further 4– 7 days.36 Antibiotics only if infection is considered (such as in an acute. Controlled trials of oral or intravenous metronidazole. patients (and their doctors) prefer to know an absolute estimate of the likelihood of colectomy.

4–17). It carries many of the risks (including nephrotoxicity) of ciclosporin. In 2001. OR 4.2.7). Results did not reach significance.1 Series S. There have been other small studies of IFX for acute severe colitis refractory to steroids that have not shown a difference in colectomy.69 5. The long-term outcome indicates that a minority avoid colectomy. after careful discussion between the patient. Tacrolimus. 58% of 76 patients64 and 88% of 142 patients65 came to colectomy over 7 years. specialist advice should be sought at an Case series of tacrolimus for steroid-refractory ulcerative colitis. This may matter if colectomy is performed. compared to 2/11 on placebo and the remainder had no response. then there is little that medical therapy can hope to offer since it is unlikely that remission can be maintained.01 mg/kg Tacrolimus oral 0. A recommendation on the best choice between calcineurin inhibitors and IFX in addition to intravenous steroids is not possible until there has been a comparative. group and 14/21 in the placebo group had a colectomy within 3 months (p = 0. It was the group with less active disease after 5–7 days of intravenous steroids who benefited most from IFX.01/oral 0. Ciclosporin (CsA).9.82 Although IFX is reported not to increase post-operative sepsis.61 Nine of 11 patients failing steroids improved on ciclosporin whilst all 9 on placebo failed to improve (RR 0. Case series have shown broadly similar results to ciclosporin after both intravenous (0.4. Infliximab. In the largest randomized study of CsA to date. 95% CI 1. with 9% coming to colectomy in the 2 mg/kg group and 13% in the 4 mg/kg group.75–77 It should be noted that hospitalized patients with severe colitis represent a very different population to the outpatients in the ACT 1 & 2 studies78 (see Section 5.017. compared to a case series of ciclosporin therapy in n Response Colectomy at 1–3mo 1 year 16/76 12/38 2/23 – 2 year 16/76 19/38 3/23 3/9 64 70 71 72 Ref similar patients Ciclosporin (iv 4 mg/kg. Infliximab as a single dose (5 mg/kg) may also be effective rescue therapy. A large controlled trial is needed.2.67 9/16 had a partial response to 0.02 mg/kg) and oral (0.5.6.2.1 to 0. If a patient has acute severe colitis despite existing treatment with an immunomodulator at an appropriate dose and duration. A placebo-controlled trial in 1994 identified CsA as potential rescue therapy for intravenous steroid-resistant UC (IVSR-UC). is a potential advantage compared to IFX. 5. The short half life of CsA.2 mg/kg) administration (Table 5. Selection.2. Travis et al. however.05 mg/kg/ day adjusted to trough levels (up to 15 ng/mL).3).50 Response rates at 8 days were similar in both groups (83% and 82% respectively).5. only 100/622 (16%) patients treated received CsA. while IFX will circulate for weeks. Many gastroenterologists will be more familiar with the adverse-event profile of IFX compared to CsA or tacrolimus.30 5. because case series report 20%. as well as the potential benefit. The effect of IFX as maintenance therapy in these circumstances is unclear: such patients are a different to those in the ACT trials and the risks. Controlled trials comparing CsA and IFX are n progress (2007/08). Tacrolimus is another calcineurin inhibitor. since septic complications are the major cause of post-operative morbidity and mortality. In general only a single attempt at rescue therapy with a calcineurin inhibitor or IFX should be considered before colectomy.P.18.5.5. it is only a matter of hours before it disappears from the circulation.4 The short term response was 51% (95% CI 41–60%) and 29% colectomy (95% CI 25–32).4.05–0. One randomised controlled trial has been performed in ulcerative colitis that included 27/60 patients with acute severe colitis.79–82 5. 3/11 and 4/9 eventually underwent colectomy in the treatment and placebo groups respectively.4.3. However. A Cochrane review66 concluded that numbers in controlled trials were so few (only 5049.73 7/24 in the IFX Table 5.2). only 17 (15%) received CsA and only 7 of 33 (21%) who came to colectomy had received CsA. but other case series report 70–80% early response.4.1).61) that there was limited evidence for CsA being more effective than standard treatment alone for severe UC. If doubt persists.15 mg/kg 76 38 23 9 56/76 18/38 22/23 9/9 10/76 3/38 1/9 . of deferring (or even avoiding) colectomy need careful discussion with individual patients. although tacrolimus is a more effective immunomodulator than ciclosporin in renal or liver transplantation (see Table 5. The Sweden Index54 on day 3 identified sicker patients at an earlier stage than the Seo Index74 calculated on day 5–7. acting through a mechanism similar to CsA (Section 5. then oral) Tacrolimus iv 0.83 no data are available that relate only to emergency colectomy for sick patients with acute severe UC (Section 7. No patient died. randomised controlled trial.7). 73 patients were randomized to either 2 mg/ kg or 4 mg/kg of intravenous CsA.L. gastroenterologist and colorectal surgeon about the options and potential outcomes. 33%.63–65 Concerns about early toxicity have been partly addressed by low dose (2 mg/kg) intravenous induction therapy (Section 5. The individual circumstances of each patient have always to be considered.62 In nine studies that used CsA as rescue therapy in the systematic review of severe colitis.68. Two different scores were used to identify patients before randomization to IFX or placebo. In two series. A Swedish–Danish study treated 45 patients (24 IFX and 21 placebo with continued intravenous betamethasone). out of the 116 consecutive patients admitted to 29 UK hospitals with severe UC.3).64).1. Consequently if CsA does not work.2 mg/kg Tacrolimus iv 0. 95%CI 0.2. The narrow therapeutic index of CsA and its side-effect profile has limited acceptability.01 to 0. 57% or 75% ultimately coming to colectomy after IFX for intravenous-steroid resistant ulcerative colitis.

84 The incidence has never been studied systematically.ECCO Consensus on UC: Current management early stage from a referral centre. but prospectively-collected cohort of patients who had avoided surgery on the index admission was reexamined after 15 years.033).2. with a view to continuing treatment as an outpatient. remission was achieved by intensive treatment within a week in 90%.1.6. A senior surgical opinion is best sought on the day of admission. Use of IFX with CsA has been associated with a particularly high rate of adverse events (see Section 7. severe colitis admitted to hospital will have toxic dilatation. followed by reassessment of the diagnosis by colonoscopy and serial biopsy. It carries a mortality of up to 50%.6.3.6.39 Other complications appear exceptional.2.89–91 In a review of 158 middle-aged or older American patients with ulcerative colitis. Earlier diagnosis of severe colitis.96 Consequently. since abnormal intestinal motility induces proximal colonic stasis in patients with distal colitis and this affects drug delivery.3).92 5. Refractory proctitis and distal colitis Refractory proctitis and distal colitis present common clinical dilemmas. In 39 patients with distal disease refractory to outpatient treatment with oral steroids and mesalazine. cerebral sinus thrombosis40 and a poorly recognised panenteritis. haemorrhage and others. the wrong drug.7) for incomplete responders (p = 0.1 and 1.2. The next step is to treat proximal constipation.7. a vigorous laxative is appropriate.0 months (CI 28.93 Median time to colectomy was 33. If symptoms do not resolve within another 2–4 weeks.001). tacrolimus. surgery is likely to be the outcome. The classic knee-elbow position may relieve distension. Crohn's.97 Should the response be poor.6–67.1) for complete responders vs 6. 5. 8/22 (36%) complete responders to steroids came to colectomy. including massive haemorrhage (1/66 patients operated on for acute severe colitis in one series88). The next step is to ensure that conventional therapy (Sections 1. The first step is therefore an empathetic review of symptoms and treatment to date. or those with visible blood in the stools at day 7. The long term outcome after admission with acute severe ulcerative colitis is not good.2.85 The key aspects of management are aggressive medical therapy and early surgical decision making.2–63. a plain abdominal radiograph is appropriate.0 cm associated with systemic toxicity. Perforation. scintigraphy showed that 91% of a labelled.2. almost invariably associated with colonoscopy or toxic dilatation where colectomy has been inappropriately delayed. distal colitis is best treated as if it was more extensive or severe. About 5% of patients with acute. It is no different to conventional therapy for acute severe colitis.3).39.082).6. the patient must realise that the steroid-free remission rate after 7 months (30 weeks) on IFX is only 21%78 (see also Section 5. but the incidence for infective colitis is rising. or very rarely. bowel preparation. undertreated. but a coherent therapeutic strategy is needed if patients (and their doctors) are not to get frustrated by persistent symptoms. except that metronidazole 500 mg three times daily is appropriate on empirical grounds in case of an infective aetiology. more intensive medical management and earlier surgery has reduced the incidence of toxic megacolon complicating ulcerative colitis. however. Perforation is the most serious complication of acute severe colitis. It should be made clear to all that there is a 24 h window of opportunity for medical treatment to work and that if there is no improvement then early colectomy will be necessary.39 so these should be corrected or avoided. Toxic megacolon. cancer). The longest period of steroid-free remission was a median 45.1. 5.2. range 0–120) for complete. When the outcome of a small.2. Refractory distal colitis responds more rapidly and better to intensive treatment than oral or topical therapies. 56% in the ACT 1&2 studies had left-sided or distal colitis.3–22. perforation or massive haemorrhage and 7/20 died. The combination of steroids and antibiotics is safe even for infective colitis. It is defined as total or segmental non-obstructive dilatation of the colon N6. mucosal prolapse.0 months (CI 12. Attention in particular should be paid to topical therapy (topical mesalazine together with topical steroids. inadequate concentrations of the active drug. after explaining the paradox of proximal constipation despite distal diarrhoea. if sigmoidoscopic inflammation persists after treatment with topical mesalazine and oral steroids.86 Nasogastric suction cannot be expected to decompress the colon and is unnecessary. Toxic dilatation and complications of severe ulcerative colitis 5. after considering suppositories and the type of enema for the distribution of disease) in conjunction with oral therapy. but if the patient is not acutely ill then the decision should never be precipitate and a range of topical or anecdotal 31 . unrecognised infection. or IFX can be tried.0 months (95% CI 0. steroids reduce inflammation in pseudomembranous colitis. compared to 8/10 incomplete responders (stool frequency N3/day. so that only 9% (95%CI 4–15) reached the distal colon compared to 31% (95%CI 24–37) in 22 healthy controls (p b 0. Eudragit-coated resin remained in the proximal colon. Data on the burden of medical and surgical treatment of severe colitis and attendant complications.94. Reasons for refractoriness include poor adherence with therapy.2) has been vigorously applied. CsA. range 1– 35) for incomplete responders (p = 0. However. 20/158 had toxic dilatation. In 12 patients with active left-sided disease. time off work. If disease persists in spite of these approaches. unrecognised complications (such as proximal constipation or infection) or inappropriate diagnosis (such as co-existent irritable bowel syndrome. Toxic dilatation (megacolon) represents the end of a spectrum of severe colitis that has been unrecognized. Long term outcome of severe colitis.39 Metabolic disturbance (hypokalaemia or hypomagnesaemia). 5. There is a tendency to opt for these treatments before admission for intensive therapy. If there is visible faecal loading in the descending colon.6. or anti-diarrhoeal therapy have been associated with toxic dilatation. but a median 8. p = 0.2. reflecting the increasing prevalence and severity of pseudomembranous colitis.017). related to patient-orientated outcomes (hospitalization. but only if there is a prospect for maintaining remission. Commonly. colectomy and mortality) are still required.9–17.87 but is generally impracticable.3.5 months (CI 4.2. a co-existent irritable bowel accounts for more symptoms than active disease.95 There are few trials on this specific population. or refractory to appropriate treatment.

5.2).5.2. A therapeutic strategy that includes consideration of how steroid-free remission will be achieved and maintained should be discussed with the patient.4).2.2. After 12 months (ACT 1). necessary speed of response. 5. Early relapse Any patient who has an early (b3 months) relapse is best started on azathioprine (AZA) or mercaptopurine (MP). 1. active ulcerative colitis Azathioprine is significantly more effective than mesalazine at inducing clinical and endoscopic remission in the treatment of steroid-dependent UC. active UC were randomised to receive AZA 2 mg/kg/day or oral mesalazine 3. 5.001). but precise definitions have not been agreed (Section 5. although surgical options should also be considered and discussed.98–134. concurrent therapy (whether a relapse occurred during treatment with immunomodulators) and adherence with maintenance therapy.4. other causes of persistent symptoms including coexistent cytomegalovirus.3).2). 408/728 (56%) were taking steroids at study entry in the two ACT studies. It is generally unnecessary to re-evaluate the distribution of disease unless this will influence medical or surgical management. A total colectomy has to be performed.4. RG C] should also be considered ECCO statement 5G Patients who relapse should usually be treated with the therapy that was previously effective [EL5. AZA should be the first choice of therapy in apparent steroid dependence. since many have to be made up individually by pharmacy. because segmental resection leaves that part of the colon most affected and is almost invariably followed by relapse affecting previously normal bowel. The timing of surgery depends on the severity of symptoms.05). The patient's gender. because the treatment strategy should think beyond the current relapse and aim to reduce the risk of a further relapse.3.2. 27 had surgery for distal disease.L. These include the views of the patient (adverse effects. use more For active UC that is refractory to steroids. biological therapy or surgery considered (Section 5.3. Infliximab is indicated if sepsis has been excluded and surgery thought inappropriate at that stage.2. or to increase maintenance therapy.32 therapies are available (Table 5. 5. but consideration should be given to other factors and maintenance therapy should be optimised. Up to 10% of patients who have a colectomy for refractory UC only have distal disease.4. All but one patient were satisfied with the results and 25/27 wished that they had had surgery sooner. 5. Immunomodulator-refractory ulcerative colitis Immunomodulator-refractory disease is also best reassessed by colonoscopy and biopsy to confirm the diagnosis and exclude complications.3. If active UC is confirmed. depending on the pattern of relapse and previous response to therapy. immunomodulators should be added and calcineurin inhibitors.136 53% on AZA achieved steroidfree clinical and endoscopic remission after 6 months compared to 21% on mesalazine (OR 4.3.2(4) vs 4. potent induction therapy. nocturnal stool frequency and urgency (p b 0.57– 14. Previously unknown severe dysplasia was identified in 2 patients. 95%CI 1. Infliximab also has a steroid-sparing effect when administered every 8 weeks for up to 1 year. Intravenous steroids. The choice depends on local availability and personal preference. The sequence (or hierarchy) of therapy has to depend on the individual circumstances and views of the patient. usually with ileoanal pouch formation (Section 7.P. 1.78. Opinion is divided whether to use the same treatment to induce remission and taper more slowly.2. 5. Treatment of relapse compared to new cases ECCO statement 5H Patients with persistently active.5. convenience.3. RG B].135 There was a significant decrease after surgery in mean (SD) diurnal stool frequency (8. Some patients have active disease that persists in spite of appropriate treatment and these are best considered as a separate group with steroid-refractory disease (see definitions). In the .3. the figures were 9% and 26% respectively (p = 0.2).2 and 2.3. The outcome of colectomy and pouch formation for distal colitis is usually good. or anti-TNF-refractory). 5. It helps management to recognise other treatment-refractory groups (immunomodulator-refractory. RG D] The initial treatment of relapse best uses the treatment that worked first time.3.2 g/day. infliximab [EL1b. Continued medical therapy that does not achieve steroid-free remission is not recommended. In 263 patients who had a restorative proctocolectomy at one French centre (1986–96). After 7 months (30 weeks).2. 1. fecundity and extent of disease should be taken into account.3.01). steroid-refractory disease should be treated with azathioprine/mercaptopurine [EL1b. Treatment according to the course or behaviour of disease Treatment decisions differ between patients at initial presentation and subsequent relapse. 72 patients with steroid-dependent. ‗Steroid-dependent‘.1. in addition to prednisolone 40 mg/day. or cancer should be considered. They represent an important group of patients who merit study. inflammatory burden and other considerations (Sections 1.78.4. age. Oral steroid-refractory ulcerative colitis 5. Clinical judgement and an honest appraisal about the impact of symptoms on the quality of life or employment are necessary.7 (2) p b 0.006) (Section 5.5).2.3). etc).4) and the efficacy of continued AZA or IFX for maintaining remission in Sections 2. S. The balance in decision-making between IFX and surgery is addressed above (Sections 1. Travis et al. RG B] or calcineurin inhibitors [EL3. timing of relapse. 10/139 (7%) on placebo and 28/130 (21%) on 5 mg/kg IFX every 8 weeks had achieved steroid-free remission (p = 0.3.

Most had refractory disease. placebo 24% (p= 0.4) in placebo Random 40 Cyclosporin 40% improvement vs placebo 45%.05) 7 Ineffective.9 (−0. needs repeating. pb 0. response in 6 patients with pancolitis Open 22 12/22 ‗excellent‘. 6 m Transdermal nicotine (15–25 mg) vs prednisolone (5–15 mg). 11/31 nicotine withdrawals (side-effects) 100 101 102 103 104 105 106 Ciclosporin enemas T-cell immunosuppression 107 Epidermal growth factor enemas Ecabet sodium enema Immunoglobulin G enemas Interleukin-10 enemas Leukocytapheresis Nicotine Epithelial restitution/repair EGF 5mcg (100 mL enema) vs placebo. intention to treat.5 (−2.03) Random 80 No difference between groups for maintenance therapy Random 61 Nicotine 21% remission vs 47% prednisolone (p= 0. 2 weeks Bismuth carbomer (450 mg) enema vs 5-ASA (2 g) enema.3 to −5. Concern about malignancy 8 Clinical activity index decreased (5.4 to 0. Rapid and promising. 110 3 Endoscopic response in refractory left-sided colitis Open 30 Clinical remission 21/30 Random 72 Nicotine 48% remission. 6 weeks Ropivacaine (400 mg) daily.2 Agent Summary of therapies for distal colitis Proposed mechanism Neuroimmune modulation Dose and duration Lignocaine (800 mg) daily.8. 6 weeks 111 112 113 114 115 (continued on next page) 33 .5 + 0.ECCOConsensusonUC:Currentmanagement Table 5.4) in colostrum group. with no recurrence for up to 3years Random 20 9/10 clinical/endoscopic improvement (refractory distal colitis). 4/22 ‗very good‘ response (refractory UC) Open 12 Clinical and endoscopic improvement (pb 0. 4 weeks Colostrum 10% (100 mL enema) vs placebo (albumin) 4 weeks Cyclosporin 350 mg vs placebo. 1/7 improved. 83% distal colitis.05) Random 33 Rectal eicosanoid & neuropeptide concentrations similar after ropivacaine in 19 distal UC compared to 14 controls Cases 16 Remission. 4 weeks Bismuth compounds Bovine colostrum Enhanced mucosal barrier? Reduced bacterial adhesion Source of growth factors for epithelial restitution 100 Remission 10% proctitis. vs +0. Potential toxicity in 6/10 (1 week) 2/10 (4 weeks) Random 63 Bismuth 39% remission. Open trials in refractory distal UC more favourable Random 24 83% remission at 4 weeks vs 8% on placebo.16) Random 14 Activity index −2.4 to +3.035). 6–34 weeks Design Open n Outcome Ref 99 Anaesthetic gel Lignocaine (600 mg) daily. 56% 5-ASA (p =0. 2 weeks Open Open Open 108 109 Immune response promoter IgG enema ? IL-10 deficiency in UC ?monocyte adsorption Smoking protective.3 + 1. IL-10 100mcg enema for 10 days Weekly for 5 weeks Transdermal nicotine (15–25 mg) vs placebo 6 weeks Transdermal nicotine vs placebo. 2 weeks Ropivacaine (200 mg) single dose Appendicectomy Arsenic Altered Th1/Th2 balance Uncertain Surgery Acetarsol (500 mg) vs prednisolone (5 mg) suppositories. 12 weeks Mucosal protection Ecabet sodium 1 g in 20–50 mL.

133 134 Wheat grass juice Prebiotic and antioxidant Triticum aestivum WGJ (100 mL) vs placebo . 6 weeks SCFA mixture vs placebo. 6 weeks Sucralfate 4 g vs prednisolone metasulphobenzoate 20 mg enemas. sucralfate 28% Random 50 5-ASA superior. 4 weeks Nicotine tartrate enemas (3–6 mg). 3 withdrawals Open 22 16/17 improved (previously unresponsive). Dose and duration Transdermal nicotine vs placebo.P. 4 weeks. 4 weeks Nicotine carbomer enemas (6 mg). Sucralfate no different from placebo Random 40 Hydrocortisone 42% remission.027) 10 5/7 improved (previously unresponsive UC). 4 weeks Ridogrel 300 mg (40 mL) Open 20 55% remission 9still on steroids) at 3 weeks Random 45 Most improved in all three groups 121 122 Sucralfate Enhanced mucosal barrier Random 40 70% SCFA clinical response. Ridrogel 300 mg vs prednisolone 30 mg enemas.34 Table 5. placebo 9% (p= 0. Open Design n Outcome Ref 116 117 Random 64 Nicotine 39% clinical response.025) compared to controls 123 124 125 126 127 128 129 130 131 132 Thromboxane A2 inhibitor Inhibition of inflammatory mediator S.2 (continued) Agent Nicotine Proposed mechanism Smoking protective. 6 weeks SCFA vs butyrate or placebo. 6 weeks Butyrate vs placebo.007) Random 30 Remission 12/15 on nicotine +5ASA enema. 4 weeks Sucralfate 10 g vs 5-ASA 2 g vs placebo 4 weeks Sucralfate 10 g vs hydrocortisone 100 mg enemas.L. (p b 0.4 g.Travisetal. 5/15 on oral 5ASA + enema (p = 0. 4 weeks PropionylL-carnitine (PLC) enemas Rebamipide Short chain fatty acids (variable composition) Epithelial (SCFA) nutrition PLC 6 g (200 mL) twice daily.031) and rectal bleeding (p =0.05) Random 60 No difference between groups Random 40 Ridrogel 65% endoscopic remission vs prednisolone 75% (no difference) Open 11 Decrease in mucosal TxB2. 4 weeks Sucralfate 20 g vs methylprednisolone 20 mg (100 mL) twice daily. 6 weeks SCFA mixture vs placebo. 20% placebo No change in endoscopic or histology scores Open 10 5/10 responded well (refractory distal colitis) Random 103 No difference in clinical or histological response Random 47 No difference between three groups Random 38 No difference Random 44 Predenema 71% cessation of bleeding. 6 withdrawals 10 8/10 ‗improved significantly‘ 120 Open 118 119 Cytoprotective proprionic Enema twice daily. 4weeks Transdermal nicotine (15 mg) with 5ASA enema vs enema +mesalazine 2. 6 weeks SCFA mixture. oral steroids continued acid Epithelial nutrition SCFA mixture vs 5-ASA or steroid enema. sucralfate 15%. but not other PGs Random 21 Decrease in activity index (p= 0.

1.4. Delivery systems can be divided into azo-compounds.1321) in the most recent meta-analysis.5 – 13.2. RG B] or surgical options should be considered. 5. Much is made of how different delivery systems may influence response. Continued medical therapy that does not achieve steroid-free remission is not recommended [EL5.4 g/d for 8 weeks. ratio of 5ASA to its metabolite N-acetyl 5ASA. There have been few clinical trials comparing the efficacy of newer aminosalicylates for inducing remission.147 Those with olsalazine143–146 or balsalazide [unpublished.4. the current section considers drug-specific aspects of treatment not addressed in that section.2–4.83.2).1 – – Eudragit-L coating. This means that drug efficacy cannot be deduced from pharmacokinetic comparisons. dissolves at pH6 Same Same 10. Systematic reviews and meta-analyses concur that aminosalicylates are effective for treating active UC.60–1. Mesalazine has a topical action on colonic epithelial cells. Six trials with mesalazine (including two trials on MMX mesalazine) show statistical significance vs placebo. Efficacy of aminosalicylates.138 Delivery system Mean peak plasma [5ASA] (μmol/L) Mean systemic exposure (AUC. and is better tolerated.5 (median) Eudragit-S coating of hydrophilic polymer with some 5ASA and lipophilic excipients encapsulating 5ASA – no published data . see ref 27] do not. The route of delivery.1. Systemic exposure is therefore unnecessary.5 – – 21.4.23. Adverse effects of aminosalicylates.4.8 Azo-bond Sulfasalazine Olsalazine Balsalazide Controlled release Pentasa® pH7-dependent Asacol® Mesren® Ipocol® pH6-dependent Salofalk® Mesasal® Claversal® Composite (‗multimatrix‘)Mezavant® (EU) Lialda® (US) Sulfapyridine carrier 5-ASA dimmer 4-amino-benzoyl-β-alanine 0.3–3.1.2 (median) – 38.140–142.3137–139). where it is also metabolised. Despite variable differences in peak serum concentrations.152 but for active UC the choice of 5ASA cannot be made on the grounds of efficacy alone. 5.4. Aminosalicylates 5. controlled release. Therapy-specific considerations The therapeutic goal should be to induce steroid-free clinical remission.7–3. Available data do not suggest a difference in efficacy between any of the 5-ASA preparations for active UC. 95%CI 0. RG D] absence of contraindications infliximab should be considered (Section 5. 24.5 2. although for the lesser target of response or remission the NNT is 4 (95%CI 3–6)22). but it is essential to keep in mind how remission will be maintained (Section 6). with Asacol and found no significant difference in remission rates after 2.9 5. Mesalazine is shown to be as effective as sulfasalazine for inducing response or remission (OR 0.27 The NNT Table 5. results for defined primary and secondary endpoints failed to demonstrate statistically significant differences.9–22. but evidence that it matters in clinical practice is remarkably thin.5 1.3) as well as colectomy. a pH7-dependent release mesalazine.151 Proprietary prescribing of mesalazine is recommended.1–10. dissolves at pH7 Same Same 2. In 2 of 3 trials of balsalazide vs mesalazine.ECCO Consensus on UC: Current management to induce remission is 10 (95%CI 7–21).6–27. but absorption might conceivably influence adverse events.5 28. dose frequency. μmol/L.3 Delivery systems for 5-ASA137.1. however.148–150 Another study compared Ipocol.h) 9.22.3 21. 5.5 Ethylcellulose coated microgranules 6. which may be most appropriate. The treatment strategy depends primarily on the activity and distribution of UC (Section 5.5–25. cost and availability are more relevant factors in the choice.21. the systemic exposure to equimolar doses of all 5-ASA compounds is similar 35 ECCO statement 5I Infliximab [EL1b.5 Eudragit-S coating. pH-dependent (either pH6 or pH7) and composite (pH-dependent combined with controlled release) (Table 5.

2% (placebo).8% and 32.75 vs 0. The primary endpoint at week 8 was response (N30% and a 3 point decrease in the Mayo activity index.36 Table 5.05) 147 (Table 5.007) 23 24 Pentasa® Hanauer 1993 Olsalazine Meyers 1987 Hetzel 1988 Feurle 1989 Zinberg 1990 Rowasa® Sutherland 1990 374 4 (95).8 vs 0. p= 0. concluded that it was effective for inducing clinical remission.4.76).P.18–4.3.155 giving an NNTof 2 (95%CI 1. Travis et al. rash (1%) and thrombocytopenia (b1%) are reported.157 5.055) Improvement 40% vs 11% (p= 0. 4.22 More recently. but the inclusion of severe colitis makes this difficult to extrapolate to outpatient therapy.1. p b 0.004) 180 6.4.14–2. 0 (36) 2.2.0% respectively) and mucosal healing . Adverse effects and monitoring of steroid therapy are the same as described in the Consensus guidelines on Crohn's disease.4.11) Improvement (ns.78 They are impressively consistent. Many clinicians believe that creatinine and full blood count should be monitored every 3– 6 months during aminosalicylate therapy. Efficacy of steroids. showing double the remission rate compared to placebo. 0 (93) 4. in seven RCTs. or placebo at 0. 5. p= 0. 1 (92). 95% CI 1. 2 (97).87).8 (38). but a systematic review has confirmed that all new 5-ASA agents are safe. Monitoring.4% (5 mg/kg) and 61. 2. and reducing the need for colectomy in the short term.5 (16). with virtual cessation of rectal bleeding). 2 (45). when 86 (out of a total of 136) newly diagnosed patients with UC were treated with steroids.0012) 142 66 30 105 15 3 (15). 0 (90) 8 29% vs 12% ( 4g vs 0. A population-based study found the risk (OR 1. 2.156 However. There have been only two placebo controlled trials of conventional oral steroids for outpatients with active UC. Corticosteroids 5.5 (73).5% vs 22.1. At one year.4 vs 0. 1.153 Acute intolerance in 3% may resemble a flare of colitis since it includes bloody diarrhoea. Patients with pre-existing renal impairment. Renal impairment (including interstitial nephritis and nephrotic syndrome) is rare and idiosyncratic. or comorbid disease should have renal function monitored during 5-ASA therapy.54–2.4.2 g × 2 (93).5% (10 mg/kg). 0 (53) 3 (7). no absolute numbers) Improvement (4/7 vs 0/8.4). CI 1.L.159–162 A single infusion of infliximab was also more effective than placebo in reducing the need for colectomy within 90 days after infusion (RR 0.65–2.41) at 8 weeks.60.44.1. 95%CI 2.75 (72). other potentially nephrotoxic drugs. then every 8 weeks for a year.29. promoting mucosal healing. 1. given IFX 5 mg/kg. 0 (86) Asacol 0. 10 mg/kg.001).22–0. Recurrence on rechallenge provides the clue. 51%. g (n) 4. 0 (20) 2 (15).8g × 3 (86) 8 8 29% vs 13% (4.009) 41.6 (11). p = 0. and 6 weeks) was more effective than placebo in inducing clinical remission (RR 3. 0 (8) 3 8 4 4 Improvement 50% vs 16% (3 vs 0.2. with adverse events that are similar to placebo for mesalazine or olsalazine.158 The review took the description of ‗severe‘ at face value and failed to discriminate between out-patients and in-patients with acute severe colitis.05) 143 144 145 146 136 4 (47).3.8g ×1 vs 0. 1.88.1% vs 32. headache (2%). ACT 1 was a 364 patient study in moderately active UC refractory to oral steroids and/or thiopurines. 1. 0 (52) Weeks 6 6 Remission (unless otherwise stated) S. This was achieved: 37. nausea (2%). clinical response.9%. Efficacy of IFX. 31% and 18% had a complete response.8 g× 1 vs 0. p b 0.6% (4.26 compared to normal) to be associated with disease severity rather than the dose or type of mesalazine. p= 0. IFX (three intravenous infusions at 0. Ref 140 141 24% vs 5% (4.28) and clinical response (RR 1.4 Placebo-controlled trials of newer aminosalicylates for active UC n Asacol® Schroeder 1987 Sninsky 1991 Balsalazide Salix (unpublished) MMx mesalazine Lichtenstein 2007 Kamm 2007 87 158 Dose.4.99. 17% were steroid-dependent.047) Response 49% vs 23% (2. p b 0. A systematic review of the efficacy of IFX for treating patients with moderate to severe UC refractory to corticosteroids and/or immunomodulators. 95%CI 1.6 (53). p= 0.154 5. It was also more effective than placebo at inducing endoscopic remission (RR 1.8 g ×1 (85).73 The ACT 1&2 studies are pivotal. Nevertheless. So too were pre-defined secondary endpoints of remission (14.4– 5). 21% had surgery and 7% lost to follow up. ns) 27 280 343 4.8 g ×1 (94). 0 (35) 4 Response 45% vs 45% (6. p = 0.22. 38. 0 (15) 2 (52). Mesalazine intolerance occurs in up to 15%.4 (53).2% vs 40.3. 0. although there is no evidence favouring one monitoring regime over another. Infliximab (IFX) 5.4 g × 1 (84). 0 (44) 6 Improvement 45% vs 18% (4 vs 0. this includes a group of 22/86 who had acute severe colitis needing intravenous treatment.75 (15). 55% were in steroid-free remission. 69.78. partial or no response respectively at 30 days. 95%CI 0. 2 and 6 weeks. Diarrhoea (3%).

Adalimumab is an anti-TNF agent similar to IFX.174–178 Data from a recent. Response (and remission) rates at week 8 were 29. compared to 14% on placebo (p=0.167 There have been five placebo-controlled trials of AZA for active UC. has shown potential in open studies for steroid-refractory UC170 another CD25 inhibitor. Adverse effects of IFX.167 or a median 146 days compared to 54 days after mesalamine enemas in another study. All aspects are considered similar to the use of thiopurines for Crohn's disease. but given subcutaneously with less immunogenicity. 5.3.89) during the trial. although no evidencebased recommendations can currently be given.3.4.4.9% and 36. p b 0.182 This is the only published comparison of MP and MTX. In the combined analysis of 484 patients with UC who received IFX in the ACT trials there were 8 who developed pneumonia.4. well conducted study on steroid-dependent active UC131 are discussed in Section 5.001).7%.4 and 1. in the 244 who received placebo there was just 1 basal cell carcinoma. 1. The flat dose-response is comparable to that of IFX for Crohn's disease.180 This prospective study on 60 patients (27 with UC) study did.0%.158 There is some evidence from a retrospective multicentre study of 1176 patients that those on AZA for UC are more likely to relapse if it is discontinued after 4 years than are patients who have Crohn's disease.3. TPMT gene expression and thiopurine metabolites. ns vs MTX). Alicaforsen is an anti-sense oligonucleotide to human ICAM1.4.0 mg/kg respectively. with differing entry criteria. A complex dose-ranging protocol in 112 patients showed that a 240 mg enema every night for 6 weeks was more effective than placebo.181–183 The only randomised placebo-controlled trial using a dose of 12.5. in common with other biological therapy there is a risk of serious infection. placebo). Dose.179 5.001).3.2. 1. only few have been applied to UC. monitoring and adverse effects of thiopurines.165 but whether this benefit is maintained remains unclear.4. is consistent with previous reports that the development of different types of toxicity is unpredictable. Methotrexate (MTX) 5. those whose disease relapses as the dose of steroid is reduced below an arbitrary 15 mg.169 Clinical remission rates at week 6 were 33% and 32% for 0.The actual role of IFX for UC refractory to conventional therapy for both outpatients and inpatients is discussed in Sections 1. Treatment with IFX is relatively safe if used for appropriate indications. was suspended in Q307 when interim analysis showed no benefit.4.2. because only 21% (at 7 months) and 26% (at 12 months) achieved steroid-free remission (see Section 5. Further analysis of the ACT 1 & 2 trial data indicates that there was an associated reduction in colectomy (hazard ratio 0.173 5. use varying doses or routes of administration and have inconsistent outcomes. 5. 5. but presenting in the trial period) and 3 neuropathies (2 optic neuritis.5 mg/kg/day and 3 g/day 5-ASA for 72 steroid-dependent patients (34 UC and 39 Crohn's) showed a remission rate at 30 weeks of 79% for MP. Intravenous MLN-02 (an α4β7 integrin antagonist) was given to 181 patients with moderately active UC. 1 multifocal motor).1. dose and duration.5).4. There are current trials in UC. but who could have moderately active UC despite 5-ASA alone (26%) and was 6 months' duration.9%. 10 mg/kg. Adverse events in the ACTstudies78 were no different to those expected from large experience of treating Crohn's disease.9%. 33.05 vs MP. Visilizumab is an anti-CD3 monoclonal antibody binding to activated T-cells to induce apoptosis.3. 5 mg/kg) and 69. Although one IL-2 receptor (CD25) inhibitor.164 Nevertheless. Thiopurines 5. This is important because the Consensus stresses the importance of achieving steroid-free remission. 1 tuberculosis and 1 histoplasmosis (who later died) as well as 4 neoplasia (all probably preexisting. of between 20 and 80 patients each. Duration of effect was maintained through week 30 in all respects (remission in 15.2% (27.158 More recent work on measuring thiopurine methyl transferase (TPMT) and ITPA genotypes.2.03). 95% CI 0.157 Unfortunately.5.ECCO Consensus on UC: Current management (33.37–0.163.1.181 The low dose may account for disappointing efficacy as well as the lack of side effects. Efficacy of azathioprine/mercaptopurine. and 59.5% (33. Tighter surveillance to detect dysplasia may be necessary. and relapse within 3 months of stopping steroids. Until more data are available it cannot generally be considered an alternative to thiopurines for steroid-resistant UC (see also Section 6. TPMT activity. 62. a large therapeutic gap persists despite being on 5 mg/kg IFX every 8 weeks.57. Immunomodulators should be started in steroid-dependent or steroid-refractory patients. however. basiliximab.2. equivalent to 3.7. but response was then maintained for 6 months in 80% compared to 44% on placebo.136. an almost identical trial of a further 364 patients. 37 . although all agree that monitoring of the full blood count before and after starting therapy is appropriate. Studies on MTX for UC are small.5.6. those who require two or more corticosteroid courses within a 12 month period. A randomized comparison of oral MTX 15 mg/ week (still a relatively low dose) with mercaptopurine (MP) 1. The same goes for ACT 2.5. find that measurement of meTIMP early in the steady state phase might identify patients at risk of developing myelotoxicity. The main role for thiopurines are as steroid sparing agents (NNT 3). Efficacy of MTX. 58% for MTX 25% for 5-ASA (p b 0. 1.3. Prolonged medical therapy for a potentially pre-malignant condition with anti-tumor necrosis factor therapy creates its own anxieties.5.4. was ineffective in a controlled trial of 159 patients with moderately active UC.171 Certolizumab has not yet been evaluated for UC.172 An American–European review on biological therapy for UC has been published.9%.168 Another selective antiadhesion molecule strategy is also effective for UC.5% (17/ 484).3% (5.3).2. Remission was only 14% at 6 weeks.6.3. By contrast. intravenous steroid-resistant UC showed a 30 day remission rate of 30% (60% response) to 5microg/kg given on two consecutive days.7%. For arbitrary but practical purposes. daclizumab.5 mg per week of oral MTX in UC showed no benefit.5%. 64. thiopurines are considered appropriate for the same indications as for Crohn's disease: patients who have a severe relapse.3.166 A Phase III study in intravenous steroid-resistant UC. A dose-ranging study in 69 patients with severe.0%). Data on thiopurines for active UC are few.5 mg and 2. p b 0. Other biological therapy Despite the proliferation of biological therapies. No recommendation can be made about routine measurement of TPMT activity or genotype prior to initiating thiopurine therapy. demyelinating disease and associated mortality. however.

and 2% lymphocytes while the latter removes up to 100% of neutrophils and monocytes. Opportunistic infection is the main concern.188 The optimal dose. increased according to the trough level after 24 hr.5 mcg/kg. either calcineurin inhibitor appears able to induce remission. Antibiotics as an adjunct to steroids do not alter the outcome of severe colitis (Section 5. 5. during which time 2–3 l of blood is drawn from one arm.8.4. 5. Calcineurin inhibitors (ciclosporin (CsA) and tacrolimus) 5. giving it a potential role in the treatment of active UC. Antibiotics. Oral dosing may be an alternative to intravenous administration but only retrospective data are available. but treatment of refractory colitis UC associated with Fusobacterium varium has been reported.67 Tacrolimus may induce diabetes mellitus. It is said that 2 h post-dose peak levels give the best estimate of drug exposure by correlating with the pharmacokinetic area under the curve185 and an appropriate target appears to be 700 ng/mL.2.4.4. Tacrolimus is more effective when given at a dose that achieves a trough concentration of 10-15 ng/m.0 mcg/kg.2. Efficacy of CsA. the pig whipworm. but there was less hypertension in the lower dose group. Travis et al. At the 2 mg/kg dose.7. Out of two small controlled trials of unfractionated heparin and three using low molecular weight heparin in up to 100 patients.4. The majority of CsA side-effects are dosedependent.4. or placebo for 12 weeks showed no consistent differences between the groups. Although this reduces the short-term colectomy rate.186 Opportunistic infections and the value of chemoprophylaxis is the topic of a separate ECCO Consensus. Adverse effects of calcineurin inhibitors. In the largest randomized study of CsA to date. with a response in 43% and 17% respectively (p = 0.05 mg/kg/day. Sessions last an hour.1. although novel delivery systems are being developed. tetracycline 500 mg and metronidazole 250 mg all three times daily improved clinical. 5. or gastrointestinal upset affect around half of patients. Leucocytapheresis.38 5.2. but 345 + 146 ng/ml with the 4 mg/kg dose. Dose and monitoring and adverse effects of MTX. only the smallest trial has shown benefit for active UC. The study was too small to show a difference in serious side effects.7. The former removes 65% of neutrophils. 55% monocytes.4.3. Expense may limit its use. or a polyester fibre filter (Cellsorba®. A trial of 60 patients randomised to weekly injections of pegylated interferon alpha at 1. S. and infused into the other arm.4. 3/30 of those treated with 2500 T suis ova every 2 weeks for 12 weeks achieved remission compared to 1/24 given placebo (ns). Hypomagnesaemia. wholeblood trough levels of 100–200 ng/ml using a monoclonal radioimmunoassay are generally considered satisfactory. First principles indicate that treatment is best continued until immunomodulator therapy (AZA/MP/MTX) is established.187 Two weeks' triple therapy with amoxicillin 500 mg.70 In practice. but this has not been correlated with efficacy for UC.67 The initial oral dose in this randomized trial of 60 steroid-refractory patients with active UC was 0.4. None had a complete response. Helminths.43–48). Otsuka Pharmaceuticals). renal impairment. transiently colonises the gut.5. Alternative therapies whose role remains to be established 5.8.50 Response rates at 8 days were similar in both groups (86% and 84% respectively).190 5. Heparin. the risk of clinical relapse remains high in the first year after treatment63–65 (see Section 6. . It appears that leucocytapheresis does something for active UC. T suis.5%) died of opportunistic infections (1 of Pneumocystis jiroveci (carinii) pneumonia and 2 of Aspergillus fumigatus pneumonia) in a series from a major specialist centre. 5.2. but quite what and how much is difficult to define.4 and 1. together with experimental evidence that several helminths moderate immune-mediated models of colitis lead to therapeutic trials of Trichuris suis ova.4.04). Heparin promotes epithelial restitution and repair in addition to anticoagulant properties. As with thiopurines. for which evidence from controlled trials supports its use.5. Hypertension. among others) and down regulates IL-13.4. Interferon alpha induces antiinflammatory cytokines ((IL-1RA. A course of treatment is typically 5–10 sessions at intervals of 1–2/week. all aspects are considered similar to Crohn's disease.192 and one large trial comparing it with sham apheresis for active UC that has yet to report. There have been a multiplicity of observational studies.4. Details of the role of CsA and tacrolimus for severe UC are given in Sections 1. 3/86 patients (3. and 20-60% lymphocytes. Leucocytapheresis involves extracorporeal removal of leucocytes through an adsorptive system of cellulose acetate beads (Adacolumn®.2. Interferon-alpha. two unusually designed randomised trials comparing leucocytapheresis with prednisolone191 or a sham column. Low dose CsA (2 mg/kg iv) induction therapy has largely addressed concerns about early toxicity. 5. but the outcome of controlled trials will govern its future role in Europe.4. 73 patients were randomized to either 2 mg/kg or 4 mg/kg of intravenous CsA. although whether either alter the longterm pattern of disease is unknown. filtered.8. In a randomised trial of 54 patients with mild-moderately active UC.P.7.1. paraesthesiae or tremor and headache are the commonest adverse events. the mean CsA concentration on day 4 was 246 + 64 ng/mL.8. compared to 8 (38%) achieving a lower trough level and 2 (10%) in the placebo group.193 It has wide-spread acceptance in Japan. endoscopic and histological scores in a randomised trial of 20 patients.158. 0.L. but is non-pathogenic in man. Suitable target levels to induce remission are not known.4. interval and duration of treatment need to be established and the response confirmed in a larger study. 13 (68%) achieving this trough level responded within 2 weeks.6.3.8.184 5.187 More evidence is needed. Dose and monitoring.7. Asahi Medical Company).8.2.2. 5. with 9% coming to colectomy in the 2 mg/kg group and 13% in the 4 mg/kg group. Observations that there is an epidemiological mismatch between UC and helminth infections.2).189 It cannot currently be recommended. but in responders on oral medication.

1.1.201. clinical relapse rates among patients receiving placebo range from 29% to 43% at 6 months. RG D]. which can be the source of confusion (Sections 5. Pattern of disease More than half of patients with UC have a relapse in the year following a flare.3). safety of maintenance treatment [EL1b.3.202 The impact of life events in relapse of UC has been examined by a number of studies199. both induction and subsequent maintenance therapy were assessed in the same trial of infliximab. disease course (frequency of flares) [EL5. and basal plasmacytosis on rectal biopsy specimens were independent predictors of relapse. In clinical trials designed for the maintenance of remission in patients with clinical remission at baseline. RG A]. 1.197 In another study of 74 patients including various biomarkers and clinical measures. Furthermore. General 6.194 A population-based study carried out in the county of Copenhagen.196–200 In one study of 92 patients.9. whether or not immunomodulators or biological therapy is used. The alternative is to define relapse as infrequent (b1/yr). and the efficacy of maintenance therapy evaluated by the secondary endpoints of clinical response.203 with contradictory results (Section 11.2. Risk factors for relapse Few prospective studies have assessed risk factors for relapse in patients with inactive UC. extraintestinal manifestations and a low-fibre diet were independent variables associated with a higher risk of relapse. 49% had a prolonged response.2. Preparation for the period after treatment of active disease A patient's response to initial therapy should be assessed within several weeks.2 Clinical relapse is defined by an increase in stool frequency and recurrence of rectal bleeding. RG B]. confirmed by endoscopy (Section 1.2. RG D]. clinically [EL1.1.196 In a second study of 64 patients. frequent (N2 relapses/y). the clinical response at week 8 was defined as the primary endpoint. while 74% had ‗moderate‘ course (two or more relapses within the first 5 years.3–13.1. the percentage of patients experiencing an ‗indolent‘ course (no relapse during the first 5 years after diagnosis) was 13%.2.195 described the outcome in1575 patients in the first 5 years following diagnosis of ECCO statement 6C Choice of maintenance treatment in UC is determined by disease extent [EL1b. and cancer prevention [EL2a. Maintenance therapy is recommended after successful medical treatment of active disease.ECCO Consensus on UC: Current management 39 UC between 1962 and 2005. the patient should continue until symptomatic remission is achieved or further improvement ceases.1. RG A] and endoscopically defined [EL2.1.1.0) among 99 patients who collected b80% of their prescriptions for maintenance mesalazine.200. RG D]. Minnesota. Adherence to medical therapy appears to be the governing factor associated with relapse. RG B] 6.1). multiple previous relapses (for women). steroids are typically not permitted as concomitant therapy. severity of the most recent flare [EL5. since the risk of relapse was more than 5-fold higher (OR 5. but less than every year). 6. In a population-based study from Olmsted County. Maintenance of remission 6. The pivotal endpoint that matters to patients is clinical remission with complete corticosteroid discontinuation in those who were receiving steroids at baseline.204 5. In such studies. and 13% had an ‗aggressive‘ course (disease activity at least every year during the first 5 years). or continuous (persistent symptoms of active UC without a period of remission)33 (Section 1. In the most recent period.6.6). RG D] Patients with disease requiring steroids probably have a different outcome to the overall population of patients with UC. If treatment is effective.5. treatment used for inducing remission during the most recent flare [EL5. 22% . because in two recent studies. 6. RG B] ECCO statement 6B Maintenance treatment is recommended for all patients [EL1a. a younger age.5. 5.1. This highlights using the term ‗moderate‘ to refer sometimes to the pattern of disease and also to the activity at a point in time. RG B]. This approach to the evaluation of maintenance therapy is not cast in stone. failure of previous maintenance treatment [EL5. RG D].198 This study did not confirm the two-fold increase in relapse rate in those with persisting active inflammation (polymorphonuclear leukocytes in the rectal mucosa) observed in two earlier histopathology studies. Intermittent therapy is acceptable in a few patients with disease of limited extent [EL5.1.2. and from 38% to 76% at 12 months.3). the outcome of 183 patients with UC diagnosed between 1970 and 1993 was analysed one year after a first course of steroids. although highly relevant from an epidemiological perspective. clinical remission and mucosal healing at weeks 30 and 54 (Section 6.78 Using this approach. The endpoint is the absence of relapse (or failure to maintain clinical remission) after 6 or 12 months.205 Among the 63/183 patients treated with corticosteroids. An outcome other than steroid-free remission after treatment of active disease is considered unacceptable.5). 95%CI 2. ECCO statement 6A The goal of maintenance therapy in UC is to maintain steroid-free remission. grouping activity into quintiles seems too long a period for everyday practice. the frequency of previous relapses. Maintenance therapy trial design Most trials of maintenance therapy for UC have enrolled patients in clinical and endoscopic remission. a shorter duration of current remission and a higher relapse frequency were predictive of further relapse.

1.4.1. 4pb0. 3Asacol/Claversal. In all but one of the trials. failure to maintain clinical or endoscopic remission was 20–48% in the active arms compared to 47–89% in the placebo arms.2.1. 2Pentasa. Oral 5-ASA.2). the difference between the two arms was significant at 3. Several RCTs have compared rectal mesalazine in various formulations and regimens Table 6.05.11 6.40 S. RG A]. Rectal 5-ASA. dosage. with a number-needed-to-treat (NNT) of 6. side effects and monitoring of aminosalicylates.215.6 1.36–0.2).P.206 Randomised controlled trials (RCTs) designed to evaluate the efficacy of oral 5-aminosalicylates (5-ASA) – including sulfasalazine. 6. 95% CI 4. The combination of oral mesalazine and intermittent rectal 5-ASA appears to provide further benefit. mesalazine and olsalazine – for maintaining remission are shown in Table 6. .05 for comparison of 5-ASA (both groups) vs placebo.2. The only RCT that failed to demonstrate efficacy of 5ASA suppositories215 followed a three times a week regimen.81.6 g/day to intermittent rectal mesalazine. and infliximab are in the Active Disease section. A combination of oral and rectal 5-ASA can be used as a second line maintenance treatment [EL1b.2). zileuton (not shown) and placebo. but only 3/183 were treated with AZA/MP (see also Section 5. 5comparison of 5-ASA.1. There have been two RCTs comparing combination treatment with oral mesalazine plus intermittent mesalazine enema to oral mesalazine alone for maintaining remission (Table 6.2.216 However. (sulfasalazine: SZP. 6 and 9 months but did not reach the significance level at 12 months.2.2. a postal survey of the UK patients showed that 80% preferred oral treatment alone. with a trend in favour of the rectal treatment (Table 6.227–237 At 12 months. olsalazine: OLZ. steroids. Maintenance with topical 5ASA is a valuable alternative in proctitis and leftsided colitis [EL1b. the differences in failure to maintain remission between active and placebo groups were statistically significant.2. Other trials have demonstrated efficacy with similar intermittent rectal 5-ASA regimens.1 Author [ref] Placebo-controlled trials of oral 5-aminosalicylates for maintaining remission in UC Year Number of patients 67 64 59 101 101 205 264 Study drug Dosage (g/day) Duration (months) 12 6 6 6 12 12 6 Failure to maintain clinical or endoscopic remission 29% 76%1 22% 55%1 29% 24% 23% 45%1 63% 69% 43% 62%1 56% 56% 71%4 40% 59%1 Misiewicz207 Dissanayake208 Riis209 Sandberg-Gertzen210 Wright211 Miner212 Hanauer213 1965 1973 1973 1986 1993 1995 1996 Hawkey214 1 1997 323 SZP Placebo SZP Placebo SZP Placebo OLZ Placebo OLZ Placebo MSZ2 Placebo MSZ3 MSZ Placebo MSZ3 Placebo 2 2 2 1 2 4 0. 0.1.9). RG A]. 5-ASA suppositories were generally well tolerated ECCO statement 6D Oral 5-aminosalicylate (5-ASA) containing compounds are the first line maintenance treatment in patients responding to 5-ASA or steroids (oral or rectal) [EL1a. Remission rates were higher in patients receiving the combination.2).6 6 pb0.207–214 6.2. Medications for maintenance of remission Details of the action. in another study in Spain. 6.3. RG B] were steroid dependent and 29% came to colectomy.7–55. showed a superiority of rectal mesalazine over placebo for remission maintenance at 1 year (OR 16. Aminosalicylates 6.62). and mesalazine: MSZ). The most recent version of the Cochrane meta-analysis showed that the Peto odds ratio for the failure to maintain clinical or endoscopic remission (withdrawals and relapses) for oral 5-ASA vs placebo was 0. thiopurines. with placebo for maintenance of remission in distal UC (Table 6. Combining oral and topical 5-ASA therapy. The data suggest that rectal 5-ASA has equivalent or slightly superior efficacy to oral mesalazine in distal UC. There are also three small RCTs comparing sulfasalazine 2 g/day or oral mesalazine 1. Travis et al.1. A meta-analysis which included the two placebo-controlled trials.47 (95% CI.L. It is therefore clear that oral or rectal 5-ASA is superior to placebo in maintaining remission in UC. either alone or in combination with oral 5-ASA. Although most authors in the studies claimed that patients found long-term rectal treatment acceptable.

219 Another trial has also reported a trend for benefit in subjects receiving the higher dose of Pentasa 3 g/ day compared with 1. Dose-response effect. p b 0.4 g/day was also performed significantly better than 1. . although adherence to prescribed therapy should be addressed. there was no increase in the frequency of adverse events. For those with extensive UC. the benefit of the higher dose was more marked (143 days vs 47 days.220 As with other studies of high doses of 5-ASA. RG A].5 g/day (p = 0. This post hoc analysis must.2 g/day (75% vs 33%. It is possible that high doses of maintenance oral mesalazine are required in some patients. be treated with caution.05. RG A]. Table 6.4.051).8 – 4 g ×7/month 4 g/3days 2g/day 4 g/day 4 g/2 days 4 g/3 days – 4 gx2/week 2g/day 4 g /3 day 1.ECCO Consensus on UC: Current management 6. but it may be debated whether this is clinically significant.5 × 2/day 0. When the results for patients in remission at 12 months were analysed after stratifying for frequently relapsing (N3 relapses per year) vs less frequent relapses. perhaps in those that required high doses of oral 5-ASA to induce remission or those with frequently relapsing disease.218 Patients taking the higher dose were in remission for longer than those on the lower dose (median time in remission of 175 days vs 129 days. Adding rectal therapy is a treatment option for patients who have relapsed on oral 5-ASA alone. respectively). other oral 5-ASA preparations are preferred for toxicity reasons. p b 0.3).2 in distal UC Author [ref] Sutherland227 Biddle228 D'Arienzo229 D'Albasio230 Randomized controlled trials of rectal mesalazine compared to placebo or oral formulations for maintaining remission Year 1987 1988 1990 1990 Number of patients 29 25 101 79 Study drugs MSZ enema MSZ enema MSZ enema Placebo MSZ suppository Placebo MSZ enema MSZ enema Oral SZP MSZ enema MSZ enema MSZ enema Placebo MSZ enema Oral SZP MSZ enema Oral MLZ MSZ enema + oral Oral MSZ alone MSZ suppository MSZ suppository Placebo MSZ suppository Placebo MSZ suppository Placebo MSZ enema + oral Oral MSZ alone Dosage (g/day) Duration (months) 6 12 12 24 Failure to maintain clinical or endoscopic remission 40% 46% 25% 85%1 20% 80%1 31% 28% 39% 19% 28% 35% 52%1 25% 40% 26% 68%1 39% 64%1 10% 32% 47%1 48% 62%2 46% 89%1 18% 77% 2 4 1 0.5/day – 3 ×1 g/week – 0. but the difference did not reach the significance level at month 12. A dose-response for maintenance of remission with mesalazine at doses greater than 0. MSZ: mesalazine.6g/day 0. RG A] and considered comfortable for treatment of at least one year. At the moment. 2pb0. SZP: sulfasalazine.6 g/day 1. however. The dose can be tailored individually according to efficacy and in some cases higher doses ± topical 5-ASA may be useful [EL5.2 g compared to 2. All the different available preparations of oral 5-ASA are effective [EL1a. RG A]. RG D]. no difference was found in relapse rates at 1 year on mesalazine 1.4 g/day. In an Italian study.217 The choice and options should be discussed with patients.2. For rectal treatment 3 g/ week in divided doses is sufficient to maintain remission.001).05 at months 3. there is no robust evidence to support the choice of any specific 5-ASA preparation for maintenance [EL1a.5 1 g ×2/week + 3 g/day 3g/day Miner231 1994 92 6 Andreoli232 Mantzaris233 D'Albasio234 D'Albasio235 1994 1994 1997 1998 31 38 69 111 12 24 12 12 Marteau215 Hanauer236 Yokoyama237 1 1998 2000 2007 95 65 24 12 24 – pb0. Although sulfasalazine is equally or slightly more effective [EL1a. 41 ECCO statement 6E The minimal effective dose of oral 5-ASA is around 1 g per day [EL1a.1–6. 2.8 g/day has not been established (Tables 6.6 and 9.005).5g/day 2 ×4 g/week + 1.1. however.

which would have minimized sulfasalazine-related adverse events.2. there is no good evidence to support this.221 There are also no data supporting a dose-response relationship with rectal 5-ASA for maintaining remission in distal UC (Table 6.3).5 2 1 2 1.222 comparing olsalazine 1 g/day head to head with oral mesalazine 1. remission rates were 75% and 54%. No controlled trial has yet been published on maintenance of remission with mesalazine MMx.5 1 2 0.75–1.2).57). because most trials enrolled sulfasalazinetolerant patients.5–2 3–4 1 1.4 12 12 46% 33%5 74% 70% Asacol/Claversal.1. although this is unlikely to have mattered (above).2 2. This study has not been replicated and the dose inequivalence noted. single-blind RCT218. and OR 1.2 0.31.05.6. respectively (p = 0.25 2 2 12 6 12 12 6 12 12 12 12 12 Ardizzone248 Kruis249 1995 1995 88 160 12 6 Nilsson250 Fockens220 Paoluzi218 1 1995 1995 2005 169 156 1. 95% CI 0.5.2 g/day as maintenance for UC.51 2 1 2 0. Sulfasalazine and 5-ASA had similar adverse event profiles (OR 1.P. .6 43% 17% 43% 26%2 40% 46% 45% 56% 49% 37% 54% 42% 54% 49% 46% 48% 25% 46%2 52% 40% 40%3 38% 51% 36% 49% 24% 32% Azad Khan238 1980 Andreoli239 Ireland240 Riley241 Mulder242 McIntyre243 Rutgeerts244 Kiilerich245 Rijk246 Courtney222 Travis247 1987 1988 1988 1988 1988 1989 1992 1992 1992 1994 13 164 92 72 79 273 226 46 99 198 SZP SZP SZP MSZ SZP OLZ SZP MSZSZP MSZSZP BLZ SZP MSZ1SZP OLZ SZP OLZ SZP OLZ MSZ1 OLZ OLZ OLZ MSZ1 SZP OLZ OLZ OLZ SZP OLZ SLZ MSZ MSZ4 MSZ1 MSZ1 1 2 4 0.16. 6. and no more than 1 g/day is necessary for rectal 5-ASA therapy.42 but at present. However. 95% CI 0.51.16.238–250 The odds ratio was 1. sulfasalazine. 2pb0. especially the rate of diarrhoea in the olsalazine group. 4Pentasa.75 1. There is only one. The frequency of adverse events was low in this study.99 respectively).82 1.220. Adherence to 5-ASA treatment.1.057.5 3 1. suggesting greater therapeutic effectiveness for sulfasalazine. 6.5 3 2 2 0. 3failure including relapses plus study withdrawals.02). with a negative NNT.3 Author [ref] S.62–2. Travis et al.29 (95%CI 1.05–1.L. perhaps because there was a predominance of patients with distal UC. unacceptable side-effects were frequent in the 3 g group. the trials that compared 5-ASA and sulfasalazine are likely to have been biased in favour of Table 6. In the Cochrane meta-analysis206 the odds ratio for the failure to maintain clinical or endoscopic remission (withdrawals and relapses) was calculated for the trials in which sulfasalazine and 5-ASA were compared (Table 6. 5p=0. Adherence to 5ASA appears to be important for improving outcome of Trials comparing different oral 5-aminosalicylate formulations and dosages for maintaining remission in UC Year Number of patients 170 Study drugs Dosage (g/day) Duration (months) 6 Failure to maintain clinical or endoscopic remission 33% 14% 9%2.86–1. At 1 year.2. Comparison of oral 5-ASA formulations.

compared to 9/11 subjects (81%) who did not receive AZA maintenance (p = 0. RG D] 6. 95% CI 2.01).1. patients who collected b80% of their prescriptions had a 5-fold higher OR (5. The results were similar when analyses were limited to patients who had successful induction of remission (data available for two studies).05) and acceptability (p b 0. Adverse effects occurred in 11/127 patients receiving AZA.63 After intravenous CsA.78. Restrospective series have suggested that thiopurines reduce the risk of colectomy after the induction period with CsA. clinical and endoscopic remission was achieved in 53% on AZA.23-25. The two open label studies that compared MP to mesalazine and AZA to sulfasalazine showed significant heterogeneity and could not be pooled.5 63–65).ECCO Consensus on UC: Current management patients with UC. Thiopurines after ciclosporin (or tacrolimus) for induction of remission. Addition or continuation of oral 5ASA can be recommended with special attention to potential myelotoxicity [EL5.2.5.262 In this series. The same group conducted a prospective study to determine the effects of non-adherence with 5-ASA among 99 patients with quiescent UC. The study quality was judged generally poor and the evidence for using thiopurines in UC is weaker than that for Crohn's disease.225 Patient questionnaires showed significantly greater compliance (p b 0. Calcineurin inhibitors are rescue therapy options for steroid-refractory UC (see Section 5. including acute pancreatitis (3 cases) and bone marrow suppression (5 cases).182.251–254 In the Cochrane meta-analysis published after the Consensus meeting.2. compared to 21% given 5-ASA (intention to treat analysis: OR 4. Thiopurines considered.175.24–0. the overall adherence rate was 40% and the median amount of medication dispensed per patient was 71% (8–130%) of the prescribed regimen.2. RG D].001) in the once daily group. Nevertheless. Steroid-free. The study has yet to be reported in full. or for use of co-medication with mesalazine in these studies. and 22% of patients taking MP required a colectomy.265 Similar results have been reported from Chicago: of 36/42 initial responders to CsA. Seven RCTs evaluating the efficacy of thiopurines azathioprine (AZA) and mercaptopurine (MP) for maintenance of remission in UC are listed in Table 6.256–262 The best among these is the 30 year cohort from the Oxford IBD clinic between 1968 and 1999.2 g/day for 6-months. the overall remission rate in the 346 patients with UC who were treated with AZA was 58%. patients were randomized to receive either once-daily or conventional (twice or three times daily). An investigator-blinded study of 362 patients randomised to receive Pentasa 2 g once daily or 1 g twice daily. of whom 20% required colectomy vs 45% who did not thiopurines during the 5 year follow up.263–265 In 1996.2.204 In a pilot study.158 AZAwas shown to be superior to placebo on the basis of four trials (OR for failure to maintain remission 0. 95% CI 1.6% respectively) in the single daily dose group. patients that are steroid-dependent [EL1a.2. Since this meta-analysis. Efficacy of thiopurines for maintenance of remission. The median time to relapse after stopping AZA was 18 months. having extensive disease or having an endoscopy within the past 24 months reduced non-adherence. even in patients who are 5-ASA naive.57–14.4. or 81% allowing for a brief relapse with a short corticosteroid course. 6.263 In another series 5/19 patients receiving AZA (26%) underwent colectomy during the follow-up.2.5). 95% CI 0.41. Azathioprine/6-MP can also be considered in a patient responding to intensive treatment with intravenous steroids for induction of remission [EL5. but given comparable efficacy between once daily and divided dosing regimes for the treatment of active UC with mesalazine MMx (Mezavant®/Lialda®) and Salofalk®. RG C]. Since calcineurin inhibitors are best discontinued within 6 months because of nephrotoxicity.224 After 6 months. compared to 72% of those not taking MP. a further RCT has been published by Ardizzone et al. AZA or MP are introduced while the patient is still on ciclosporin (CsA) or tacrolimus and steroids are being tapered. This is the best trial to date.3– 13.5). p = 0. mesalazine for maintenance of remission in UC.2. the usefulness of the oral 43 ECCO statement 6F Azathioprine/mercaptopurine is recommended for patients who have experienced early or frequent relapse while taking 5-ASA at optimal dose or who are intolerant to 5-ASA [EL5. 6. a series of 29 patients successfully treated with ciclosporin were followed for a median 92 weeks. When the adherence rate in 94 outpatients on 5-ASA with clinically quiescent UC for at least 6 months was studied.136.63. with a view to acting as a ‗bridge‘ until the therapeutic effect of AZA is achieved. Evidence in support of the thiopurines for UC also comes from observational cohorts in retrospective series.255 six of these studies on 286 patients were .223 Logistic regression identified a history of four or more prescriptions and male gender increased the risk of non-adherence. This premise appears correct. There was no clear evidence of a dose-response effect for AZA. After 12 months.8% vs 63. a switch to oral therapy occurs as soon as a clinical response has been achieved. these agents are generally proposed as induction therapy until slower-acting immunomodulators such as AZA or MP become effective.07). but increased to 87% among patients on therapy for more than 6 months.2.136 72 patients with active steroid-dependent UC were randomised (investigator-blind) to AZA 2 mg/kg/day or mesalazine 3. RG A] and for patients responding to ciclosporin (or tacrolimus) for induction of remission [EL3. patients in the once-daily arm appeared more satisfied with their regimen and consumed more medication than those in the conventional arm (90% vs 76%.70). showed a 12% better remission rate at 1 year (73. RG D]. 25 (69%) also received MP or AZA. The proportion of patients in remission at 5 years was 62% applying a strict definition of relapse. Being married. The justification of thiopurines in this setting. Section 5.2. is the high colectomy rate (36-69% in the 12 months following introduction of CsA.226 the effect is likely to be generic rather than compound-specific.0). The authors concluded that once-daily oral formulations of 5-ASA were likely to be a better therapeutic option due to their ability to offer comparable efficacy and improved adherence.

In azathioprine naïve patients responding to infliximab induction. without oral ciclosporin. In ACT 1. The Leuven experience described 142 patients. but the probability increased to 88% at 7 years if CsA was used in patients already on AZA. a beneficial effect of AZA (given to 35/56 who could tolerate it) could not be demonstrated either to maintain remission or prevent colectomy (ns). 72% and 77% at 1.5–2 mg/kg/day after 3 months Placebo – Azathioprine 100 mg/day Placebo – 6–mercaptopurine 1 . 3 and 5 years. remission rates at week 54 were 35% (5 mg/kg). patients included in this study were in remission on azathioprine for at least 6 months (withdrawal design). remission rates at week 30 were 26% (5 mg/kg).1).3.P. The rate of colectomy in those already on AZA compared with those starting AZA concurrently with CsA was 59% vs 31%. RG A]. After 5 years 47% in the non-AZA and 40% in the AZA-treated patients came to colectomy.2.3.266 Cumulative probabilities of relapse were 42%. and 90% within 3 years 90%. a significantly higher proportion of patients had a clinical response or remission on IFX at weeks 8 and 30 (and at week 54 in the ACT 1 trial). RG D] 6.mg/kg/day Placebo Azathioprine4 Placebo Azathioprine + SZP SZP Azathioprine MSZ – 2. Infliximab (IFX) ECCO statement 6G In a patient responding to infliximab.5 mg/kg/day Methotrexate 15 mg/week MSZ 3g/day Azathioprine4 2. and cumulative probabilities of colectomy were respectively 29%.3. In a retrospective series from Barcelona. Consequently CsA has little role for patients who have failed AZA of an appropriate dose and duration. The proportion of patients with a sustained clinical remission at all time points was 7% (placebo) and 20% (5 mg/kg) after 54 weeks . In both studies.1. infliximab is recommended for maintenance treatment [EL1b. Efficacy for maintenance. CsA bridge has been challenged. so the authors concluded that the ‗bridging step‘ with oral CsA may not be necessary. Three retrospective studies have assessed the long term outcome of patients after an attack of UC treated with intravenous CsA.44 Table 6.64 Unusually.05). In 76 patients treated with CsA for intravenous steroid-refractory UC. This needs more investigation. non-responders to IFX were taken into account in the calculation of week 30 and week 54 response or remission rates. Randomized trials of thiopurines compared to placebo or oral 5-aminosalicylates for maintaining remission in UC Year Number of patients 1974 80 Study drugs Dosage Study design Duration Failure to (months) maintain clinical or endoscopic remission 121 60% Jewell175 Azathioprine Hawthorne251 Mate-Jimenez182 1992 672 2000 34 Sood252 2000 50 2.5 mg/kg/day – 2 .63–65 All describe a high rate of relapse and colectomy.4. These are similar to or better than those reported in the literature. Moreover. azathioprine is an option instead of infliximab for maintenance [EL5. 6. The design of these studies was different to standard maintenance trials (Section 6.4 Author [ref] S. Patients included in the maintenance phase were not necessarily in steroid-free clinical or endoscopic remission. all responders to iv CsA were treated with AZA. co-medication with 5-ASA was permitted and taken by 82% of patients.05.5 mg/kg/day then reduced to 1. and after 7 years the overall colectomy rate was 58%.65 64/118 (54%) subsequently required colectomy. In ACT 2.5 mg/kg/day + 6 g/day 6g/day 2 m g/kg/day 3. respectively (p b 0.2.L. 34% (10 mg/kg) and 17% (placebo). 36% (10 mg/kg) and 11% (placebo). Life-table analysis showed that 33% of patients required colectomy at 1 year.78. 65% relapsed within 1 year. compared to placebo. 35% and 42%.1.2g/day Double-blind Double-blind Open label 12 181 Single (patient)blind Double-blind Open label 181 121 77% 36% 59%3 50% 85% 93%3 44% 60%3 23% 56% 77% 44%3 47% 79%3 Sood253 Sood254 2002 35 2003 25 121 Ardizzone136 2006 72 Single (Investigator)blind 6 1Inclusion 2All of patients with active disease who initially received steroids for induction of remission. Details of the ACT 1 & 2 studies are given in Section 5. Travis et al. 3 pb0. 118 (83%) of whom had an initial response to CsA and avoided colectomy during initial hospitalization. 4Co-medication with sulfasalazine 6 g/day in all patients.

273 Consequently. whether maintenance IFX (with or without thiopurines) is better than thiopurines alone to prevent relapse and avoid late colectomy cannot be deduced.270 Short-term combination (6 months) appears to offer a good balance between risks and efficacy for those in whom IFX is continued. 19% (10 mg/kg) and 10% (placebo). Three RCTs have compared the E. Table 6.269 These results should still be interpreted with caution. In the first study. 120 outpatients in a multicentre. the report of eight cases of a rare form of hepatosplenic T cell lymphoma occurring in young patients treated concurrently with IFX and thiopurines must also be taken into account. RG C] As with Crohn's disease. Results from a single centre open-label randomized. or premedication with steroids. or 200 mg/day of E.2. Whether IFX acts as a bridge to remission that is maintained by thiopurines. RG A] E. is currently recommended in order to decrease immunogenicity [EL3. and 2% (placebo) and 15% (5 mg/kg) after 30 weeks in ACT 2.5). coli strain Nissle (corresponding to 25×109 viable E.5g/day Probiotic mixture1number 100 mL Treatment2 Lactobacillus GG 18 × 109 Mesalazine 2. a reasonable option is to determine whether remission ECCO statement 6I E.267. those receiving corticosteroids at baseline) and those who were ―not corticosteroid-refractory‖.274 No concomitant medications were permitted. study received 1. Subsequently 116 patients with active UC were randomized to receive either 5-ASA 2.5 Author [ref] Randomized trials of probiotics for maintaining remission in UC Year Number of patients Study drugs Dosage Duration (months) Failure to maintain clinical or endoscopic remission 16% 12% 73% 73% 45% 36% 27% 90%3 15% 20% 16% Kruis274 Rembacken275 Kruis276 Ishikawa277 Zocco278 1997 1999 2004 2000 2006 120 116 327 21 187 E. After 12 weeks. because circulating concentrations of IFX declined over time when the immunomodulator was discontinued. remains debated. without committing that patient to maintenance IFX.3. . which is the source of infusion reactions and loss of response. and then 200 mg/day. This strategy has not yet been tested in UC. the corresponding values at week 30 (7 months) were 18%. because relatively few patients relapsed. Probiotics 45 ECCO statement 6H Combination of infliximab with an immunosuppressant for at least 6 months.573) presented after the Consensus meeting. coli bacteria) for 4 days.4 g/day Combination 4 12 12 12 12 1Bifidobacterium 2Open bifidum+Bifidobacterium breve+ Lactobacillus acidophilus. label study.272 The 2 year follow up of patients who received a single dose of IFX as rescue therapy for intravenous steroid-refractory UC (Section 5.2.275 All patients also received an initial 7 day course of oral gentamicin and either rectal or oral steroids in variable doses. the question of discontinuing the immunomodulator has been addressed by the Leuven group for Crohn's disease.4 g/day. coli Nissle is an effective alternative to 5-ASA for maintenance [EL1b. steroid-free remission at week 54 was achieved in 24% (5 mg/kg). coli Nissle 200 mg/day Mesalazine 1. The steroid-free remission rates in the 74 patients receiving corticosteroids at baseline were very modest although still statistically significant.e. 6. The rates of clinical response and remission were similar between the subpopulations of patients who were ―corticosteroid-refractory‖ (i. reducing to 1.4. double-blind. but is an acceptable option for thiopurine-naive patients with steroid-dependent Crohn's disease.2 g/day after remission. coli strain Nissle 1917. 6. coli Nissle 200 mg/day Mesalazine 1.2g/day E. The statistical power was limited by the short duration of the study.2g/day E. If a patient is naïve to AZA when given IFX. coli strain Nissle. showed that 13/16 patients who received AZA avoided colectomy (with or without oral 5-ASA) compared to 5/8 who received 5-ASA alone (ns). coli strain Nissle 1917 (Mutaflor®) to mesalazine for maintenance of remission in UC (Table 6.2.ECCO Consensus on UC: Current management in ACT 1. or whether AZA simply slows the rate of descent to inevitable relapse (the ‗parachute‘271). On the other hand.158 the combination of IFX and a thiopurine analogue or corticosteroids is probably justified to decrease immunogenicity. In ACT 1. coli Nissle 200 mg/day Mesalazine 1.. 27% and 3%. In ACT 2. withdrawal trial suggest that the immunomodulator can be stopped after 6 months with no loss of response to IFX over 2 years.268 Since antibodies to IFX occur early in the treatment. will be maintained by AZA alone.2. Combining IFX and immunomodulators.5 g/day 5-ASA or 100 mg/day E. but an 11–16% relapse rate within 3 months seems rather high. 11% of patients receiving 5-ASA and 16% of those receiving the probiotic patients relapsed.

Other treatments 6. 6. There were fewer relapses in the treatment arm (27% in the milk group vs 90% in the controls). Treatment failure was the primary end point. suggesting that some patients with UC may respond well to methotrexate. coli group (ns) after weaning off steroids.275 327 patients with UC in remission for no longer than 12 months were treated with either 5-ASA 1.8%. double-blind clinical trial.277 neither investigators nor patients were blinded.5 mg/week) that is probably sub-therapeutic (see Section 5.294 The pooled analysis showed a similar relapse rate in the n-3 treated patients and controls (RR 1.183. however.96). Another group of 187 patients with UC in remission for less than 12 months were randomised to receive either Lactobacillus GG 18 ×109 viable bacteria/day.279 In a randomized. This is a very high relapse rate for reasons that are unclear. 5/11 patients had a colectomy vs 5/31 patients who were intolerant of AZA (p b 0. and 68% in the corticosteroid plus E. No significant side effects were noted. 6. A significantly higher proportion of patients achieved remission in the MP group (79%) than in the 5-ASA group (25%). metronidazole was found to be slightly more effective than sulfasalazine.L. coli strain Nissle 1917 is not inferior to the established standard 5-ASA for maintenance of remission in UC. coli group (ns). but no differences in endoscopic lesions.3. The results are heterogeneous and it is possible that the dose of MTX is an important determinant of efficacy. but the Consensus considered that there is currently insufficient evidence to recommend MTX for UC.297 which included 138 UC patients who were in remission at the time of recruitment.181 The proportions of patients who relapsed after first remission (MTX 64% vs placebo. One study distinguished between patients given MTX for AZA-intolerance and AZA-failure.31. Preparations containing omega-3 fatty acids and eicosapentaenoïc acid in particular.5.2.5. The protective effect of appendicectomy for the development of UC appears to be limited to patients who undergo appendicectomy before age 20 years and is mainly observed for primary appendicectomy . MTX and 5-ASA in 72 steroid-dependent IBD patients.6 g/day) and sulfasalazine (2 g/day) were compared for maintenance of remission in 40 patients with UC in remission for less than 12 months.03.2. The relapse rate was 45% in the E. 95%CI 0. The potential benefit of adding ciprofloxacin to conventional therapy has been investigated.05).51–2. These data are regarded as insufficient by the Consensus to recommend antibiotics for maintenance of remission in UC. MTX 15 mg/week. B. Other probiotics.280 Consequently ciprofloxacin should not be considered effective for maintaining remission in UC. Patients on prednisone were randomly assigned in a 2:2:1 ratio to receive oral MP 1 mg/kg. Most had failed or been intolerant of AZA and were treated with MTX at various doses and routes of administration.46 The remission rate was 75% in the corticosteroid plus 5-ASA group. acidophilus YIT 0168 was given to 21 UC patients over 1 year. an equivalence study was conducted.4. It was concluded that E.2. Methotrexate.2.206 6. and other treatments could be administered. but the probiotic was no less effective than 5-ASA.2.01).25–0. including 34 with UC182 (Table 6. Appendicectomy. treatment with Lactobacillus GG appeared to prolong the relapse-free time compared to 5-ASA. Finally. and L.000 person-months on Lactobacillus GG alone and 181/10 000 person-months on 5-ASA (p= 0. An open-label study compared MP. definition of clinical response and concomitant therapies have been criticized. Antibiotics. Relapse rates at 12 months were 136/10. particular.4).287 Several studies have been conducted in UC with different formulations and dosing of n-3 fatty acids. 6. p = 0.5. 95%CI 0. 6. Data on methotrexate (MTX) for maintenance of remission in UC are few. In a post-hoc analysis. All the patients were initially treated with a high but decreasing dose of prednisone and with 5-ASA. 5-ASA 2.278 There were no differences in sustained clinical or endoscopic remission rates at 6 and 12 months between the three treatment groups. placebo-controlled.38. no paraesthesiae were reported. or 5-ASA 3 g/day. No other probiotic has been subject to properly powered RCTs. the higher rate was found in the MP group (64%) compared to MTX (14%) and 5-ASA (0%). Travis et al. No significant adverse events were recorded. although the relapse rate in this last study was still higher than expected. breve YIT 4065. or the combination. 44%) were not significantly different. relapse occurred in 73% of the 5ASA group and 67% of the E.282–285 to a total of 91 patients.291.02). Omega-3 fatty acids (fish oil). In another double-blind. randomized trial.5.4.293.6). Of those treated with MTX after failure with AZA.2.0001). The treatment failure rate was 21% in the ciprofloxacin-treated group and 44% in the placebo group (p=0. which is within the equivalence range of 20% required for acceptance of the non-inferiority hypothesis.5 g/day) or placebo was administered for 6 months to 83 patients referred with active UC refractory to conventional treatment. A meta-analysis included 13 case-control studies and suggested that appendicectomy gives a 69% reduction in the risk of developing UC (OR 0. The single RCT was principally designed for induction of remission in refractory. metronidazole (0.281 After 1 year. During the one year follow up. The corresponding one-sided upper 95% confidence interval for the difference in treatment was 12. When 100 ml/day of fermented milk containing Bifidobacterium bifidum YIT 4007. All patients who achieved remission at week 30 were then included in a maintenance study for 76 weeks. defined as both symptomatic and endoscopic failure to respond.285 MTX (median oral dose 20 mg/week) was tolerated by 27/31 (87%) patients who had been unable to tolerate AZA. and in S.1. may have anti-inflammatory properties by reducing the production of leucotriene B4286.4.5. active UC and used a dose (12.P. ciprofloxacin (1–1.298 The influence of potential confounders such as smoking was excluded. with no statistical differences compared to the MTX group (58%).5 g/day or E. Too many questions were being addressed by this study for conclusions on the relative efficacy of MP and MTX in UC to be drawn.02. coli group vs 36% in the mesalamine group. The study design was more appropriate for an induction rather than a maintenance study and inclusion criteria. For maintenance of remission. Several retrospective series have also been published. Further studies are needed.288–296 Only three randomized controlled trials were selected for a Cochrane meta-analysis published after the Consensus. Studies have focused on the role of appendicectomy in the UC pathogenesis. The response or remission rates ranged from 40% to 75%. pb 0.4 g/day.1. coli Nissle 1917 for 1 year.2.

The debate about the merits of 5-ASA for chemoprevention of colorectal cancer is covered in Section 9. with a less marked year-by-year disease activity and a decreased risk of colectomy. General Surgery for ulcerative colitis has been refined to offer patients needing colectomy a better quality of life.303 Patients were randomized to oral Asacol® 1.301. an Italian double-blind withdrawal RCT included 112 patients with UC in clinical. although the gain in quality of life compared to proctocolectomy with a conventional stoma seemed clear enough. In patients with disease remission for 1–2 years.302 There are only anecdotal data on the course of UC when appendicectomy is performed after UC diagnosis. natalizumab. but also because the trend was in favour of continuing mesalazine. the duration of follow-up only 6 months and patients were selected on clinical symptoms without endoscopic or histologic criteria. etanercept. offering patients an unchanged body image with no stoma and a preserved anal route of defaecation. endoscopic and histological remission who had been on sulfasalazine or 5-ASA for at least 1 year. no recommendation can be given for the duration of treatment with azathioprine or infliximab. interleukin 10. basiliximab. the gold standard for surgery was proctocolectomy with an ileostomy. IPAA is probably one of the most frequently described procedures in colorectal surgery. visulizumab. or if a patient has been taking 20 mg or more of prednisolone for more than 6 weeks [EL 4. the number of patients was small. tacrolimus. Twenty-six years later.5. RG D] In 1973. Duration of maintenance therapy ECCO statement 6J The general recommendation is to continue 5-ASA maintenance treatment long-term [EL3b. but despite this good quality evidence in terms of randomised studies are scarce (5 on different aspects of pouch surgery). apart from the sporadic use of ileorectal anastomosis. refractory colitis. Despite the small numbers. The results of this study should be regarded with caution. 6.1. Surgery for acute severe colitis ECCO statement 7A A staged procedure (colectomy first) is recommended in the acute case when patients do not respond to medical therapy [EL 4. as is so often the case in surgery. This protective effect was additive to that of current smoking.2).2. RG C] . certolizumab. mesalazine appeared significantly more effective than placebo for preventing relapse at 12 months (Asacol® 23% and placebo 49%. 47 ECCO statement 6 K Due to lack of evidence. RG C].299 The outcome of 41 UC patients with an appendicectomy before diagnosis and 466 with no previous surgery. Adalimumab. In the UK study. who have explored the subject in detail and shown an association between previous appendicetomy for appendicitis and a mild course of extensive colitis. Section 5. or 18% vs 26%.035).2.5.4. sigmoidoscopy and rectal biopsy were used at entry. 58 reviews). Biological and other therapy. Similar results have been reported from the Brisbane group.2. There have been a vast number of publications (498 papers.300 Previous appendicectomy has a beneficial effect on the course of UC. Section 9. no statistically significant difference was observed between relapse rates (5/28 vs 6/ 23.1). RG C] since this may reduce the risk of colon cancer [EL4. In the Swedish study. Section 5. respectively). not only because of the low power.304 In the past 20 years.2 g/day or placebo for 1 year. who were all prospectively included in an IBD database.5.2. and nor have leucocytapheresis. Surgery 7. but numbers were very small.306 This section deals with some aspects on surgery for ulcerative colitis. fontolizumab (an anti-interferon γ antibody).ECCO Consensus on UC: Current management (surgery for appendicitis) and not for incidental appendicectomy (removal of the appendix for other reasons). two studies from Sweden and the UK were published to assess whether sulfasalzine was still effective at preventing relapse in UC patients with a long duration of remission (Table 6. more than 2 years however.5.3. bowel function is not restored to normal and both functional outcome and quality of life after IPAA have still to be compared to living with an ileostomy. the new gold standard has become the restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA). Technical considerations 7.2. anti-IL12 and anti-IL6 antibodies have not yet been evaluated for maintenance of remission in UC. The Kock continent ileostomy was introduced in the late 1960 s.4.209 However. Until the early 1980 s. RG D] 7. daclizumab.103 Consequently. alicaforsen (an anti-ICAM1 antisense molecule). dysplasia or cancer. the authors found no statistical benefit to maintaining sulfasalazine for patients who had been symptom-free on sulfasalazine for more than a year. patients were stratified according to the length of disease remission prior to randomization. although prolonged use of these medications may be considered if needed [EL4. but never achieved universal acceptance. but no influence on the pattern of primary sclerosing cholangitis. For patients who had been in remission for 7. even in the subgroup of patients who had been on sulfasalazine for more than 3 years. p = 0. has been compared.208 The authors found that maintenance treatment with sulfasalazine 2 g/day continued to have a major effect at reducing relapse. 6. or cyclophosphamide in any meaningful way. The indications and timing of surgery for UC are found in the appropriate sections (acute severe colitis. the Consensus considered that there is no enough evidence to recommend appendicectomy for preventing relapse in UC.305 Nevertheless.1.

but not necessarily in practice. All these eventualities mean being able to hand-sew the anastomosis.310 Closing the stump and leaving it within the subcutaneous fat is as safe. a very short length of mucosa (b1 cm) above the dentate line would exclude many (or even most) male patients from the stapling technique.311 There are no studies that give information on the risk of subsequent inflammation or bleeding after leaving differing lengths of rectum or rectosigmoid colon. but the mucous fistula gives the patient another stoma that is not so easily managed. additional costs and a prolonged time under surgical care. due to technical problems achieving a low anastomosis in the narrow male pelvis. The alternatives are to divide the rectum at the level of the promontory (i. perhaps. below). RG C] Since the stapling technique commonly leaves epithelium which may still have malignant potential. When the rectum is transsected within the abdominal cavity at the level of the promontory. A subtotal colectomy with an ileostomy will cure the patient from the burden of the colitis. Anastomostic technique for restorative proctocolectomy ECCO statement 7B When performing a colectomy for ulcerative colitis in emergency circumstances. Subtotal colectomy is a relatively safe procedure even in the critical ill patient. at the proper rectosigmoid junction) or to leave in addition the distal part of the sigmoid colon. facilitating subsequent identification and dissection. because no closed bowel is left within the abdomen. There is then seldom room for re-stapling and the only way of avoiding a permanent stoma is to hand-sew the anastomosis. with pouch dysfunction and a risk of dysplasia or (very rarely) cancer. The latter option is considered very safe. anastomosis at the dentate line is recommended [EL4.2. this removes all of the potentially diseased (and pre-malignant) mucosa. this might influence the subsequent risk of cancer.P. In theory. the literature reports cancers both in patients with a stapled anastomosis as well as in . as this will render subsequent proctectomy difficult.L.3.314 However. RG C] ECCO statement 7D When performing an IPAA it is mandatory that the surgical team can also perform a mucosectomy and a hand-sewn anastomosis should the stapled anastomosis fail [EL5. or to bring the bowel up through the abdominal fascia either closed in the subcutaneous fat. Stapling is generally inappropriate when performing IPAA for dysplasia or cancer complicating colitis. or inappropriate.2. Both have to be balanced against the advantage of the stapling technique. These might have a bearing on the complication rate and have technical implications when the patient comes to a later proctectomy. permanent ileostomy. Leaving as little rectum as possible (i. Managing the rectal remnant S. since the Consensus is to remove all mucosa (Statement 7E. Whether to preserve additional recto-sigmoid colon and how to deal with bowel closure is left to the surgeon´s decision [EL 4. then this warrants transanal rectal drainage for some days. Thus patients have to go through additional surgery which incurs further risks.5. Travis et al.e. to prevent blow out of the rectal stump due to retention.e. which gives patients better nocturnal continence. with a probable increase in the risk of pelvic nerve injury.2.4. This can be a cause of persistent inflammation (‗cuffitis‘). Site of anastomosis for restorative poctocolectomy ECCO statement 7C When performing pouch surgery.48 A staged proctocolectomy (subtotal colectomy first) is considered by many surgeons to be a wise first step in the surgical treatment of ulcerative colitis in acute severe colitis or if patients are saturated with steroids. 7. This allows the bowel to be either anchored to the anterior abdominal wall.. the whole rectum should be preserved [EL 4. dividing the middle rectum within the pelvis) is not to be recommended. This is probably even wiser today when medical therapy for acute severe colitis is prolonged for more than 5 days. or brought forward as a mucous fistula.. normalise nutrition and give the patient time to consider carefully the option of an IPAA or. RG D] Nevertheless. 7. the alternative is to perform a mucosectomy from the dentate line. Consequently if the indication for proctocolectomy is cancer complicating colitis. Site of anastomosis for neoplasia complicating colitis There are some technical aspects on how to deal with the rectum when performing an emergency subtotal colectomy.2. the maximum length of anorectal mucosa between the dentate line and the anastomosis should not exceed 2 cm [EL 4. is impossible. 7. allowing them to regain general health.307–309 However it is seldom considered the final solution.2. although the skin is probably best be left to heal through secondary intention in order to avoid wound infections.313 7.312 On the other hand. the stapling technique occasionally fails. RG C]. ECCO statement 7E When the indication for surgery is cancer or dysplasia and restorative proctocolectomy is performed. RG C] The now commonly used stapling technique for performing the ileo-anal anastomosis usually leaves a remnant of anorectal mucosa above the dentate line. A preliminary subtotal colectomy also allows the pathology to be clarified and Crohn's to be excluded.

Whether the consequences of a leak can be ameliorated by a covering ileostomy or not is still under debate.1). RG D] General follow-up of people with an IPAA is a matter of debate. A total mesorectal excision is.2. 7. patients operated on for cancer or dysplasia should be followed long term [EL5. These patients will need continuing specialist care. or refractory pouchitis. poses an additional problem compared to the hand-sewn IPAA.316 7.2. it has been shown that institutions performing larger numbers of operations have better outcomes than those who only operate on such cases occasionally. however. There are no data to suggest that lack of follow-up incurs any risk for the patient. However the remaining mucosa represents a very minute fraction compared to the original colon. Number of procedures to maintain competency 7. RG D] ECCO statement 7J There are not enough data to give a recommendation on surveillance of pouches with respect to malignant changes.3. General pouch follow up ECCO statement 7I Follow up should be individualised and focus on those patients with signs of chronic inflammation in their mucosa [EL 5. Follow-up 7. However. but considered reasonable by surgical members of ECCO. However. because primary care physicians or generalists will not have the expertise necessary for management.317. although it is impossible to quantify a ‗reasonable number‘. Reported series of pouch rescue surgery describe a salvage rate above 50% and a still acceptable functional outcome.2. Fewer than 30 pouch cancers have been reported (2007). it seems appropriate that salvage surgery which is even more challenging should only be performed in units with a substantial case volume load and expertise. The number of reported cancers is limited (b30 out of tens of thousands of IPAA performed world wide) and is not at present a matter for alarm. The stapled IPAA where there is a varying length of mucosa below the anastomosis (see statement 7C. disregarding the debate on the risk of cancer.ECCO Consensus on UC: Current management those who have had a mucosectomy. but it seems reasonable to assume that this holds for pouch surgery and the figure of ten per year for the unit is arbitrary. but almost exclusively in those who had pre-existing malignancy in the resected colon.3. but sometimes the reason is a missed diagnosis of Crohn's disease with fistulation. when performing a coloanal anastomosis after rectal excision for cancer. with or without pouch excision. Pouch surveillance ECCO statement 7G An institution performing pouch surgery should do more than ten cases per year [EL 5 RG D] When performing complex surgical procedures that also demand sophisticated perioperative care.318 There are some small comparative studies.3.6.323–327 If pouch surgery is sufficiently complex to recommend a minimum case-load each year for a unit. mandatory when the indication is dysplasia or cancer. above). but it can be avoided in selected cases [EL 3b. failure rates for IPAA will probably be in the region of 15%. Before deciding that a pouch has failed.315.322 There are no details pertaining to IPAA. and also the complication that might jeopardise the final outcome of the operation. as long as there have been no problems constructing the anastomosis.316 When there is colonic dysplasia alone rather than cancer. which may be recurrent or persisting. Salvage surgery for pouches ECCO statement 7H Salvage surgery for complications of IPAA should only be done in special centres with adequately skilled staff and a reasonable number of procedures performed per annum [EL5.1. Failures are usually due to septic complications or persistent pouch dysfunction.7. such as when there is a thick abdominal wall and a short small bowel mesentery. since these patients in principle have not had a curative procedure. in pouch surgery it is sometimes clear at the time of surgery that the morbidity associated with a stoma will not justify its use. 7. RG C] One of the main complications of IPAA surgery. A proportion of patients (perhaps 20–30%) will develop pouchitis (Section 8. 49 ECCO statement 7F When performing a restorative proctocolectomy for ulcerative colitis a covering loop ileostomy is generally recommended. Role of covering ileostomy for restorative proctocolectomy From the perspective of a lifetime.8. it is now established that a covering loop ileostomy reduces the risk of clinical leakage. The patient will invariably have a view on this and it should only be undertaken by colorectal surgeons with special expertise in this area.2. is a leak in the suture lines of the anastomosis or pouch. which does not represent a risk or clinical problem for most patients. the literature gives no advice on whether to staple or perform a mucosectomy. but no definitive answer. almost all in patients operated with . the option of salvage surgery either as a corrective procedure or a complete ―redo‖ has to be considered.319–321 7. Nevertheless. RG D] The risk of malignant changes arising from the pouch mucosa as a result of colonic metaplasia in the pouch has generated much debate. Failure implies that the patient has an ileostomy for an indefinite period.

325.5.5.333 The magnitude of this problem is under debate. Age ECCO statement 7 M No defined age limit for performing an IPAA can be recommended [EL 5.4.346–348 Furthermore a failed pelvic pouch can still be converted to a continent ileostomy.337 The risk is highest at the first delivery. unlike IPAA. Females that have given birth carry a higher risk of poor continence. since the inflamed colon has been removed. On the other hand. rectal sensation. which is the basis of the recommendation for mucosectomy (statement 7E. multiple deliveries have been shown to prolong pudendal nerve terminal motor latency.328 S. above). Impact of pelvic surgery on fecundity ECCO statement 7K In a fertile female patient the option of an ileorectal anastomosis should always be considered.1. does not impair fecundity and can be discussed as a temporising option. However.329–332 The reason for this is most probably adhesions affecting the fallopian tubes.50 dysplasia or cancer already present in the specimen at primary surgery.3. or when the IPAA fails for other reasons than pouchitis. There is however good evidence from a study on patients with familial adenomatous polyposis. this group experienced very little or no difference in early postoperative continence and bowel function.4. but remains undefined. probably because sub-clinical injuries add to age-related changes in nerve function.335 This appears to be because an IRA does not induce pelvic fibrosis to nearly the same extent as an IPAA.343–345 7.349 A major problem is that this operation is still performed at only a few centres in Europe. showing that there is no reduction in fecundity associated with an IRA. provided the rectum is not grossly inflamed. Surgical choices in addition to restorative proctocolectomy 7.L.338. general population. Many of the cancers originate from anorectal mucosal remnant. Fertility and delivery in patients with a restorative proctocolectomy 7. with a view to later pouch surgery when the family is complete. collagen elasticity and muscle strength.339 People with an IPAA have a very limited margin for maintaining faecal continence compared to the The continent ileostomy (‗Kock pouch‘) was the forerunner to the IPAA. with one study showing N70% reduction and the others demonstrating around 30% reduced fecundity. are absent in people with an IPAA. RG B] It has been convincingly demonstrated in three cohort studies that female fecundity or fertility is reduced after IPAA. such as solid stools. Continent ileostomy ECCO statement 7N The continent ileostomy is still a viable option that can be used when there is no possibility of performing an ileal pouch anal anastomosis. Consequently they rely heavily on their sphincter for maintaining continence. Travis et al.340 Although it suggests that vaginal delivery is safe in selected cases. offering fertile female patients an IRA. recto-anal nervous interplay through a recto-anal inhibitory reflex.336. RG C] ECCO statement 7L With regard to bowel function a caesarean route of delivery in a female with an IPAA is recommended [EL 5. .2. Principally on these grounds many surgeons recommend that their patient have a caesarian section rather than a vaginal delivery. Consequently it is reasonable to consider whether an upper age limit for IPAA should apply. On the other hand. providing an alternative in those patients that absolutely cannot accept a conventional stoma.5.334. It has however been demonstrated that IPAA will function reasonably well in people 70 years of age and older in carefully selected cases. it remains contrary to two other papers that support the recommendation for caesarian delivery both in Europe and the US.5% risk of inflicting serious maternal sphincter tears.5–3.341.315 The frequency of small bowel cancers in the background population is very low and the risk of developing a pouch cancer de novo is likely to be as uncommon. The persisting risk of rectal malignancy is discussed in Section 7.314.1. Nevertheless. This has lead to a modification in practice at some centres.4.5. in a cohort where caesarian section was recommended only for obstetric reasons. Mode of delivery for patients with restorative proctocolectomy 7.342 7. IRA does not disturb sphincter function. 7. or when the patient specifically requests this solution [EL 4.P. This is because many factors considered important for normal continence.2. Symptoms are less when there has been a colectomy. because fecundity is at risk after IPAA [EL3b. with a functioning continent ileostomy patients report excellent quality of life with a next-to-normal body image. RG D] Faecal continence in both men and women deteriorates with increasing age. but the rectum can be expected to remain inflamed. comparing women with an ileo-rectal anastomosis (IRA) with those with an IPAA. Not every woman is a candidate for this approach. RG D] Vaginal delivery has a 0. It is a complex procedure with a high potential for complications affecting the valve mechanism that provides continence.

RG B] Minimally invasive surgery is gradually being incorporated into colorectal practice and is a feasible alternative for many patients. 7. there are not enough data to make any recommendation on whether or not the pouch should be removed [EL5. very careful discussion with the patient about increased risks of sepsis and pouch failure is appropriate. For those in whom it is considered an option. surveillance of the retained rectum is appropriate. with half of the patients still living with an IRA after 10 years. Pouch excision after pouch failure ECCO statement 7S In indeterminate colitis or colonic IBD yet-to-be classified. RG C]. corticosteroids should be weaned if possible Uncontrolled or retrospective series indicate that patients taking N20 mg prednisolone for N6 weeks have an increased risk of surgical complications. although it can be left in situ if the patient so wishes [EL5.360 The rate of steroid reduction after colectomy for acute severe colitis depends on the dose .5. Laparoscopic pouch surgery 51 ECCO statement 7O An ileorectal anastomosis should be considered only in special cases (such as for reasons of fertility) [EL4. Although one group has reported outcomes equivalent to those with UC for patients with a pre-operative Crohn's diagnosis. the question arises whether there is any reason for rectal excision.359. recent series show a better than expected durability. Therefore. The morbidity of pouch excision is probably no less than for proctectomy. RG D] The literature gives no direct guidance in this matter. Perioperative prednisolone ECCO statement 7T Prednisolone 20 mg daily or equivalent for more for more than six weeks is a risk factor for surgical complications [EL3b.1. Surgery and medication ECCO statement 7Q In a patient where the pouch has failed and there is no hope of re-establishing the anal route of defecation. Pouch surgery for indeterminate colitis. Some of these patients do not have any further pouch-related problems. 7.324 For individuals who 7. RG C] An ileorectal anastomosis is historically burdened.3.5.6. No randomised studies have yet shown any major differences from open surgery. It is not only non-curative.5. it gives shorter scars but there is no evidence for additional benefit to the patient [EL 2a. Terminology is discussed in Section 5.350. those with a secondary diagnosis of Crohn's disease are burdened with very high complication and failure rates. disconnected pelvic pouch.358 Pouch surgery for patients with a definitive diagnosis of Crohn's disease cannot be recommended. The balance is between the risk of a cancer in the disconnected bowel and the inconvenience and risks of a proctectomy.4.355 7.ECCO Consensus on UC: Current management 7. RG C] About 10% of patients with colitis will not have a definitive diagnosis that discriminates between Crohn's and ulcerative colitis. although others find no significant differences. Ileorectal anastomosis have had severe septic complications. Some patients that come to colectomy with an ileostomy as a first operation get accustomed to living with a stoma and have very few problems from their retained rectum.357 In most series that report outcome after pouch surgery. it is reasonable to assume that the risk of pelvic nerve injury is increased.5. provided that surgeons are adequately trained in this technique. none had pre-operative small bowel or perianal disease.1). Cancer surveillance of the rectal remnant after colectomy ECCO statement 7R Laparoscopic restorative proctocolectomy with an IPAA is a feasible operation. 7. There is as yet no evidence that the risk of malignant change is increased in the disconnected pouch. RG D] The dilemma is similar in the patient with a failed. but also leaves patients with the likelihood of persistent symptoms from refractory rectal inflammation and a risk of later cancer. 7.356. or IBD yetto-be classified ECCO statement 7P For patients who have a colectomy and ileostomy.6. There are reports of less favourable outcomes when performing pouch surgery for patients with indeterminate colitis.352.5.4. an IPAA can be offered with the information that there is an increased risk of complications and pouch failure [EL4.353 Options of proctectomy or surveillance of the retained rectal remnant should be discussed with the patient. If a patient has no wish for further surgery. Even so.7.351 Its role in the management of women facing surgery before they have completed their family is discussed above (Section 7. Taking out the rectum is a major operation with a considerable surgical morbidity with wound healing problems and risk of sexual dysfunction both in women and men.354.6.5. It can be assumed that the cancer risk with medical therapy and surveillance is at least less than in those who have not had surgery.

Minimal Invasive and Colorectal Surgery. then it will be more severe in the presence of circulating anti-TNF antibody.2) before IFX. 1. 18% for extensive disease at diagnosis. Such therapy in combination in an endeavour to avoid colectomy carries high risks and cannot be recommended.02). Spain and Israel. and another had severe post-operative sepsis resistant to anti-bacterial therapy and only responding to intensive antifungal treatment.1 to 39. another became jaundiced and another developed herpetic oesophagitis. RG D]. Whilst it is generally accepted that elective surgery for Crohn's disease in the presence of IFX is not associated with higher rates of sepsis.P. characterised by hypotension. In a Scottish survey 13/39 patients came to colectomy after IFX treatment for acute severe colitis. and severity of colitis were factored into the analysis. Inhibition of TNF by infliximab (IFX) or other agents could potentially lead to serious post-operative complications. The 10 year colectomy rate was 2% for proctitis/distal disease. Department of Surgery. France . The extent of disease did not differ between northern and southern centres. Hospital Huriez. but when 3 consecutive populationbased IBD cohorts from Copenhagen (1962–2005). where there has traditionally been a high rate of colectomy.8%. in a 781 patient European inception cohort (199193) from 7 countries.7. azathioprine. while there are no sufficient data yet available for infliximab Azathioprine does not appear to increase the risk of surgical complications although debate continues. none. the overall 10 year cumulative risk of colectomy was only 8. significantly less than earlier reported. with rates as high as 35% at 5 years and 42% and 54% at 10 years for extensive colitis. As a general guide.360–363 7. and 39% for the 11% (62/557) patients with proctitis progressing to extensive colitis during follow up. Milder symptoms may be disguised as a ‗slower than normal‘ recovery from surgery. Academic Medical Center. 7. or IFX (mean 2 infusions. IFX remained significantly associated with infectious complications (OR 2.367–369 It is unclear whether the overall rate is changing.L. IFX and non-IFX respectively. even in areas with excellent population-based data such as Copenhagen. Tel Hashomer 52621. p = 0. Israel Jean Frédéric Colombel. if patients have been on corticosteroids for b1 month. probably reflecting concern that all medical options were explored before surgery.6–7. Any recommendations of the rate are arbitrary. a reduction of 2.6. Colectomy for ulcerative colitis immediately following or in the medium term after the use of ciclosporin appears to have no higher rate of postoperative complications [EL2b. RG C]. Similar concerns have been raised from the Mayo clinic relating to IPAA after IFX.7%.5).370 This might reflect an increasing prevalence of proctitis and milder initial course diagnosed in the 1990s. Perioperative anti-TNF therapy TNFα is a key player in the immune response.83.5. PO Box 22700.5 mg/d each week is probably more appropriate. This is as likely to explain the low overall colectomy rate as are cultural differences or acceptance of symptoms between countries. Studies published in the early 1990 s reported an overall colectomy rates of 23%. range 0.6.365 One patient died from E. 95%CI 1. or 557/745 patients). but the aim is to avoid acute steroid withdrawal (‗Addisonian‘) crisis.01) complications were more common in IFX patients.7% and 48. Italy. it is still likely that should a septic complication occur. 59037 Lille.82 There has also been a worrying report of 20 patients receiving ciclosporin (for a mean 3.1– 6.5% for Greece. then a dose reduction of 1 mg/week (or even more slowly) is advisable. ECCO statement 7U Pre-operative azathioprine does not increase the risk of postoperative complications [EL3b.3 years. were assessed the cumulative surgery rate in 1575 patients with ulcerative colitis did not decrease significantly. Dept of HepatoGastroenterology. Colectomy in practice The rate of colectomy varies according to the patient cohort. corticosteroid dose. 95% CI. Perioperative azathioprine S. while for the occasional patient on steroids for longer than 6 months. For patients on steroids for 3–6 months.2. p b 0. IFX patients were younger than non-IFX patients (mean age 28. 47 patients received IFX before IPAA.371 Colectomy rates for extensive colitis at diagnosis in Denmark. 7.1% compared to 8. When patients diagnosed with UC in Copenhagen during 2003– 2005 were followed prospectively only 6% of patients underwent surgery during the year of diagnosis. Even if IFX does not increase the risk of sepsis.01) and infectious (p b 0. This illustrates the need for caution when using IFX in the perioperative period of severe colitis.3. 28% and 34% after 10 years of follow up. a reduction from 20 mg/day after colectomy of 5 mg/day each week is generally appropriate. Overall surgical morbidity was similar (61. There is little science to steroid withdrawal. Norway and the Netherlands were 22.7. but the prevalence of proctitis or distal colitis was remarkably high (75%.8 months. For those on steroids for 1–3 months.7). pouch-specific (p = 0. One patient who initially responded to infliximab died of septic shock from bronchopneumonia 3 weeks after treatment.364 the same may not apply to emergency colectomy for acute severe colitis (Section 5. with no mortality.10). There is particular concern that emergency colectomy within a few weeks of infliximab may be associated with more septic complications. steroids can usually be stopped abruptly after surgery without ill effect. coli septicaemia.5– 12. Travis et al.5). 1100 DE Amsterdam Yehuda Chowers. hyponatraemia and hypoglycaemia in its most severe form.52 and duration of steroids prior to surgery. Rue Michel Polonovski.195 Nevertheless. and 254 patients received Contributors Willem Bemelman. duration of follow up and geographical location.366 Between 2002 and 2005.001).2. Gastroenterology Chaim Sheba Medical Center. When age. Dept. range 1–3) before ciclosporin for severe steroid-refractory colitis. Multivariate analysis revealed IFX as the only factor independently associated with infectious complications (OR 3. Anastomotic leaks (p = 0.

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